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1. Bi-allelic ATG4D variants are associated with a neurodevelopmental disorder characterized by speech and motor impairment

Author: Marie Morimoto, Vikas Bhambhani, Nour Gazzaz, Mariska Davids, Paalini Sathiyaseelan, Ellen F. Macnamara, Jennifer Lange, Anna Lehman, Patricia M. Zerfas, Jennifer L. Murphy, Maria T. Acosta, Camille Wang, Emily Alderman, Undiagnosed Diseases Network, Sara Reichert, Audrey Thurm, David R. Adams, Wendy J. Introne, Sharon M. Gorski, Cornelius F. Boerkoel, William A. Gahl, Cynthia J. Tifft, and May Christine V. Malicdan
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or “primed” by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.
Published: 2023
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2. Position paper of the undiagnosed diseases network international with respect to the establishment of the journal Rare-Open research in rare diseases

Author: William A. Gahl, Olaf Bodamer, Helene Cederroth, Roberto Giugliani, Eric Klee, Manuel Posada De La Paz, Olaf Horst Riess, and Domenica Taruscio
Subjects: Medicine, Genetics, QH426-470
Published: 2023
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3. Essential list of medicinal products for rare diseases: recommendations from the IRDiRC Rare Disease Treatment Access Working Group

Author: William A. Gahl, Durhane Wong-Rieger, Virginie Hivert, Rachel Yang, Galliano Zanello, and Stephen Groft
Subjects: Medicine
Abstract: Abstract Background Treatments are often unavailable for rare disease patients, especially in low-and-middle-income countries. Reasons for this include lack of financial support for therapies and onerous regulatory requirements for approval of drugs. Other barriers include lack of reimbursement, administrative infrastructure, and knowledge about diagnosis and drug treatment options. The International Rare Diseases Research Consortium set up the Rare Disease Treatment Access Working Group with the first objective to develop an essential list of medicinal products for rare diseases. Results The Working Group extracted 204 drugs for rare diseases in the FDA, EMA databases and/or China’s NMPA databases with approval and/or marketing authorization. The drugs were organized in seven disease categories: metabolic, neurologic, hematologic, anti-inflammatory, endocrine, pulmonary, and immunologic, plus a miscellaneous category. Conclusions The proposed list of essential medicinal products for rare diseases is intended to initiate discussion and collaboration among patient advocacy groups, health care providers, industry and government agencies to enhance access to appropriate medicines for all rare disease patients throughout the world.
Published: 2021
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4. Hermansky-Pudlak syndrome and oculocutaneous albinism in Chinese children with pigmentation defects and easy bruising

Author: Bradley Power, Carlos R. Ferreira, Dong Chen, Wadih M. Zein, Kevin J. O’Brien, Wendy J. Introne, Joshi Stephen, William A. Gahl, Marjan Huizing, May Christine V. Malicdan, David R. Adams, and Bernadette R. Gochuico
Subjects: Bruising, Chinese, Dense granule, Hermansky-Pudlak syndrome, Hypopigmentation, Oculocutaneous albinism, Medicine
Abstract: Abstract Background Determining the etiology of oculocutaneous albinism is important for proper clinical management and to determine prognosis. The purpose of this study was to genotype and phenotype eight adopted Chinese children who presented with oculocutaneous albinism and easy bruisability. Results The patients were evaluated at a single center; their ages ranged from 3 to 8 years. Whole exome or direct sequencing showed that two of the children had Hermansky-Pudlak syndrome (HPS) type-1 (HPS-1), one had HPS-3, one had HPS-4, and four had non-syndromic oculocutaneous albinism associated with TYR variants (OCA1). Two frameshift variants in HPS1 (c.9delC and c.1477delA), one nonsense in HPS4 (c.416G > A), and one missense variant in TYR (c.1235C > T) were unreported. The child with HPS-4 is the first case with this subtype reported in the Chinese population. Hypopigmentation in patients with HPS was mild compared to that in OCA1 cases, who had severe pigment defects. Bruises, which may be more visible in patients with hypopigmentation, were found in all cases with either HPS or OCA1. Whole mount transmission electron microscopy demonstrated absent platelet dense granules in the HPS cases; up to 1.9 mean dense granules per platelet were found in those with OCA1. Platelet aggregation studies in OCA1 cases were inconclusive. Conclusions Clinical manifestations of oculocutaneous albinism and easy bruisability may be observed in children with HPS or OCA1. Establishing definitive diagnoses in children presenting with these phenotypic features is facilitated by genetic testing. Non-syndromic oculocutaneous albinism and various HPS subtypes, including HPS-4, are found in children of Chinese ancestry.
Published: 2019
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5. Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development

Author: Kristin M. Ates, Tong Wang, Trevor Moreland, Rajalakshmi Veeranan-Karmegam, Manxiu Ma, Chelsi Jeter, Priya Anand, Wolfgang Wenzel, Hyung-Goo Kim, Lynne A. Wolfe, Joshi Stephen, David R. Adams, Thomas Markello, Cynthia J. Tifft, Robert Settlage, William A. Gahl, Graydon B. Gonsalvez, May Christine Malicdan, Heather Flanagan-Steet, and Y. Albert Pan
Subjects: pheta1, ipip27a, ocrl, endocytosis, undiagnosed disease, Medicine, Pathology, RB1-214
Abstract: A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, pheta1 and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient. This article has an associated First Person interview with the first author of the paper.
Published: 2020
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6. The NIH Undiagnosed Diseases Program: bonding scientists and clinicians

Author: William A. Gahl, Cornelius F. Boerkoel, and Manfred Boehm
Subjects: Medicine, Pathology, RB1-214
Abstract: Summary The majority of the biomedical research workforce and funds are focused on studying common diseases and the development of drugs to treat them. However, some of the most remarkable discoveries in physiology and medicine are uncovered by studying rare conditions, because the importance of certain molecular mechanisms is revealed only when their dysfunction results in disease. In 2008, the National Institutes of Health (NIH) launched the NIH Undiagnosed Diseases Program (UDP), which recruits and selects patients who suffer from diseases of unknown etiology, and studies their causes at the clinical, genetic and cellular levels. In this Editorial, we discuss how the UDP has enabled the discovery of several new diseases and disease mechanisms through collaborations between clinical and basic science teams, using the power of both clinical medicine and biological models. Establishing programs with similar infrastructure at other centers around the world could help to benefit patients, their families and the entire medical community, by enhancing research productivity for rare and novel diseases.
Published: 2012
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7. Two Novel Mutations Identified in an African-American Child with Chediak-Higashi Syndrome

Author: Kerry Morrone, Yanhua Wang, Marjan Huizing, Elie Sutton, James G. White, William A. Gahl, and Karen Moody
Subjects: Medicine
Abstract: Background. Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, immunodeficiency, coagulopathy and late-onset, progressive neurological dysfunction. It also has an “accelerated phase” characterized by hemophagocytic lymphohistiocytosis (HLH). The disease is caused by mutations in the CHS1/LYST gene located on chromosome 1, which affects lysosome morphology and function. We report the case of an African-American child with CHS in Case. This 16-month old African-American girl presented with fever and lethargy. The proband had pale skin compared to her parents, with light brown eyes, silvery hair and massive hepatosplenomegaly. Her laboratory evaluation was remarkable for pancytopenia, high serum ferritin and an elevated LDH. Bone marrow aspirate revealed large inclusions in granulocytes and erythrophagocytosis consistent with HLH. Genetic evaluation revealed two novel nonsense mutations in the CHS1 gene: c.3622C>T (p.Q1208X) and c.11002G>T (p.E3668X). Conclusions. Our patient is one of the few cases of CHS reported in the African American population. We identified 2 nonsense mutations in the CHS1 gene, the first mutation analysis published of an African-American child with Chediak-Higashi Syndrome. These two mutations predict a severe phenotype and thus identification of these mutations has an important clinical significance in CHS.
Published: 2010
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8. Clinical and molecular features of 66 patients with musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS- CHST14)

Author: Kosuke Mochida, Anne Slavotinek, Roberto Mendoza-Londono, Parul Jayakar, Kiyoshi Kikkawa, Luis E. Figuera, Andreas R. Janecke, Hiroko Morisaki, Takaya Nakane, Nicol C. Voermans, Delfien Syx, Tetsuyuki Kobayashi, Tomoko Kobayashi, Toshihiro Ohura, Klaas J. Wierenga, Tomomi Yamaguchi, Takayuki Morisaki, Mari Minatogawa, Michihiro Kono, William A. Gahl, Judith D. Ranells, Ai Unzaki, Tomoki Kosho, Cynthia J. Tifft, Yoko Aoki, Masumi Ishikawa, Ohsuke Migita, Akiharu Kubo, Naomichi Matsumoto, Fransiska Malfait, Chiho Tokorodani, Yves Lacassie, Tohru Sonoda, Yvonne Hilhorst-Hofstee, Alessandra Maugeri, Glenda Sobey, Noriko Miyake, Ken Ishikawa, Anupriya Kaur, Hiroshi Kawame, Human genetics, and ACS - Atherosclerosis & ischemic syndromes
Subjects: Joint hypermobility, medicine.medical_specialty, Acrogeria, business.industry, human genetics, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Dermatology, Hypotonia, musculoskeletal diseases, Ehlers–Danlos syndrome, Genetics, medicine, Joint dislocation, Craniofacial, medicine.symptom, Hypertelorism, Palmar crease, business, Genetics (clinical)
Abstract: BackgroundMusculocontractural Ehlers−Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated.MethodsWe collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations.ResultsSixty-six patients in 48 families (33 males/females; 0–59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype–phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE.ConclusionThis first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.
Published: 2022
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9. Novel CUL3 Variant Causing Familial Hyperkalemic Hypertension Impairs Regulation and Function of Ubiquitin Ligase Activity

Author: Harish E. Chatrathi, William A. Gahl, Achim Werner, Jason C. Collins, Lynne A. Wolfe, Thomas C. Markello, David R. Adams, and Prashant Sharma
Subjects: medicine.medical_specialty, Hyperkalemia, biology, Kinase, business.industry, Pseudohypoaldosteronism, medicine.disease, Endocrinology, Blood pressure, Ubiquitin, FAMILIAL HYPERKALEMIC HYPERTENSION, Internal medicine, Internal Medicine, medicine, biology.protein, medicine.symptom, business, Gene, Function (biology)
Abstract: Familial hyperkalemic hypertension is caused by pathogenic variants in genes of the CUL3 (cullin-3)-KLHL3 (kelch-like-family-member-3)-WNK (with no-lysine [K] kinase) pathway, manifesting clinically as hyperkalemia, metabolic acidosis, and high systolic blood pressure. The ubiquitin E3 ligase CUL3-KLHL3 targets WNK kinases for degradation to limit activation of the thiazide-sensitive NCC (Na-Cl cotransporter). All known variants in CUL3 lead to exon 9 skipping (CUL3Δ9) and typically result in severe familial hyperkalemic hypertension and growth disturbances in patients. Whether other variants in CUL3 cause familial hyperkalemic hypertension is unknown. Here, we identify a novel de novo heterozygous CUL3 variant (CUL3Δ474–477) in a pediatric familial hyperkalemic hypertension patient with multiple congenital anomalies and reveal molecular mechanisms by which CUL3Δ474–477 leads to dysregulation of the CUL3-KLHL3-WNK signaling axis. Using patient-derived urinary extracellular vesicles and dermal fibroblasts, in vitro assays, and cultured kidney cells, we demonstrate that CUL3Δ474–477 causes reduced total CUL3 levels due to increased autoubiquitination. The CUL3Δ474–477 that escapes autodegradation shows enhanced modification with NEDD8 (neural precursor cell expressed developmentally down-regulated protein 8) and increased formation of CUL3-KLHL3 complexes that are impaired in ubiquitinating WNK4. Proteomic analysis of CUL3 complexes revealed that, in addition to increased KLHL3 binding, the CUL3Δ474–477 variant also exhibits increased interactions with other BTB (Bric-a-brac, Tramtrack, and Broad complex) substrate adaptors, providing a rationale for the patient’s diverse phenotypes. We conclude that the pathophysiological effects of CUL3Δ474–477 are caused by reduced CUL3 levels and formation of catalytically impaired CUL3 ligase complexes.
Published: 2022
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10. Survivorship Issues in Adult Patients With Histiocytic Neoplasms

Author: Marcus Y. Chen, Edmond J. FitzGibbon, William A. Gahl, Skand Shekhar, Fady Hannah-Shmouni, Beth Solomon, Rahul Dave, Leora E. Comis, Juvianee Estrada-Veras, Kevin O'Brien, and Bernadette R. Gochuico
Subjects: Adult, Erdheim-Chester Disease, medicine.medical_specialty, Weakness, Adult patients, business.industry, Survivorship, Adult Langerhans Cell Histiocytosis, Disease, Prognosis, Histiocytosis, Langerhans-Cell, Oncology, Neoplasms, Histiocytoses, Survivorship curve, medicine, Humans, Survivorship Issues, Histiocytosis, Sinus, medicine.symptom, Intensive care medicine, business, Histiocyte
Abstract: Adult-onset histiocytoses (AOH), primarily Rosai-Dorfman disease (RDD), Erdheim-Chester Disease (ECD), and adult Langerhans cell histiocytosis (ALCH), are a group of related histiocytic neoplastic disorders featuring multisystemic manifestations. The disorders are largely incurable, and are essentially chronic neoplastic diseases with a variable prognosis. Prompt diagnosis and treatment is important to prevent debilitating and even life-threatening complications. Survivorship issues abound in AOH, due to their multisystemic manifestations and the sometimes recalcitrant chronic inflammation, which can lead to other debilitating complications such as fatigue, weakness, and pain. Because these disorders are rare, few healthcare professionals are proficient in their management; therefore the aim of these guidelines is to offer guidance on how to manage patients, and how to create survivorship care plans through the efforts of an interdisciplinary team.
Published: 2021
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11. Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11

Author: Thomas A. Ravenscroft, Jennifer B. Phillips, Elizabeth Fieg, Sameer S. Bajikar, Judy Peirce, Jeremy Wegner, Alia A. Luna, Eric J. Fox, Yi-Lin Yan, Jill A. Rosenfeld, Jonathan Zirin, Oguz Kanca, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanya, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo Moretti, Paolo M. Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Paul J. Benke, Eric S. Cameron, Vincent Strehlow, Konrad Platzer, Rami Abou Jamra, Chiara Klöckner, Matthew Osmond, Thomas Licata, Samantha Rojas, David Dyment, Josephine S.C. Chong, Sharyn Lincoln, John H. Postlethwait, Joel Krier, and Hugo J. Bellen
Subjects: 0301 basic medicine, Craniofacial abnormality, Mutation, Missense, 030105 genetics & heredity, Biology, Article, Frameshift mutation, Craniofacial Abnormalities, 03 medical and health sciences, medicine, Animals, Humans, Missense mutation, Craniofacial, Allele, Zebrafish, Genetics (clinical), Loss function, Genetics, medicine.disease, biology.organism_classification, Phenotype, Spine, Growth Differentiation Factors, 030104 developmental biology, Bone Morphogenetic Proteins
Abstract: Purpose Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. Methods We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. Results Patients with variants in GDF11 presented with craniofacial (5/6) , vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6) and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) alleles whereas the missense variants in our cohort are partial LOF variants. Conclusion GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.
Published: 2021
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12. Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies

Author: Rachel I Gafni, Eric Yuen, Dirk Schnabel, M Zulf Mughal, Kristina Kintzinger, Carlos Ferreira, Qing Liu, Mary E. Hackbarth, Geneviève Baujat, Gus Khursigara, Pedro Huertas, Ulrike Botschen, Yvonne Nitschke, Frank Rutsch, and William A. Gahl
Subjects: Pediatrics, medicine.medical_specialty, Osteomalacia, Phosphoric Diester Hydrolases, business.industry, Endocrinology, Diabetes and Metabolism, Infant, Rickets, medicine.disease, Generalized arterial calcification, Ectopic calcification, Arterial calcification, Hypophosphatemic Rickets, Mutation, medicine, Humans, Orthopedics and Sports Medicine, Familial Hypophosphatemic Rickets, Multidrug Resistance-Associated Proteins, Pyrophosphatases, Vascular Calcification, business, Survival analysis, Calcification
Abstract: Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.
Published: 2021
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13. Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Author: Felix Marbach, Georgi Stoyanov, Florian Erger, Constantine A. Stratakis, Nikolaos Settas, Edra London, Jill A. Rosenfeld, Erin Torti, Chad Haldeman-Englert, Evgenia Sklirou, Elena Kessler, Sophia Ceulemans, Stanley F. Nelson, Julian A. Martinez-Agosto, Christina G.S. Palmer, Rebecca H. Signer, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennett, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Daya, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Joel B. Krier, Grace L. LaMoure, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Calum A. MacRae, Ellen F. Macnamara, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Paolo Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Deepak A. Rao, Wendy Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, C. Ron Scott, Daryl A. Scott, Vandana Shashi, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, null Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Marisa V. Andrews, Dorothy K. Grange, Rebecca Willaert, Richard Person, Aida Telegrafi, Aaron Sievers, Magdalena Laugsch, Susanne Theiß, YuZhu Cheng, Olivier Lichtarge, Panagiotis Katsonis, Amber Stocco, and Christian P. Schaaf
Subjects: 0301 basic medicine, Apraxias, Autism Spectrum Disorder, Pain, Biology, Apraxia, Article, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Pregnancy, Intellectual Disability, Intellectual disability, medicine, Humans, Missense mutation, Global developmental delay, Genetics (clinical), Genetics, medicine.disease, Phenotype, Human genetics, 030104 developmental biology, Neurodevelopmental Disorders, Autism spectrum disorder, Cyclic AMP-Dependent Protein Kinase RIbeta Subunit, Female, 030217 neurology & neurosurgery
Abstract: Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
Published: 2021
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14. Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study

Author: Melanie Quintana, William A. Gahl, Levent Bayman, Scott A. Van Wart, Colleen Jodarski, Claire T. Driscoll, Chia-Ying Liu, Nuria Carrillo, Carla Ciccone, Galen O. Joe, Scott M. Berry, Rebecca Parks, John D. Heiss, Bradley Class, May Christine V. Malicdan, Kennan Bradley, Petcharat Leoyklang, Joseph A. Shrader, John Perreault, Christopher S. Coffey, Christina Slota, and Marjan Huizing
Subjects: Adult, medicine.medical_specialty, Phases of clinical research, Gastroenterology, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Muscular Diseases, N-Acetylmannosamine, Internal medicine, medicine, Humans, In patient, Adverse effect, Myopathy, Genetics (clinical), 030304 developmental biology, 0303 health sciences, business.industry, Hexosamines, GNE MYOPATHY, N-Acetylneuraminic Acid, Clinical trial, Distal Myopathies, chemistry, Mechanism of action, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: PURPOSE To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. METHODS We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. RESULTS Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p
Published: 2021

15. Adult diagnosis of congenital serine biosynthesis defect: A treatable cause of progressive neuropathy

Author: Carlos Ferreira, William A. Gahl, Kelly A. King, Ariane Soldatos, Ellen Macnamara, Tanya J. Lehky, Monique C King, Sarah Debs, Edward W. Cowen, H. Jeffrey Kim, Melissa A. Merideth, Catherine Groden, C.M. Owen, Laura H Brown, and Camilo Toro
Subjects: Adult, 0301 basic medicine, Limb Deformities, Congenital, 030105 genetics & heredity, Bioinformatics, Compound heterozygosity, Article, Congenital Abnormalities, Serine, 03 medical and health sciences, Seizures, Exome Sequencing, Genetics, medicine, Humans, Transaminases, Genetics (clinical), Exome sequencing, Muscle contracture, Sphingolipids, Fetal Growth Retardation, Ichthyosis, business.industry, Neurodegeneration, medicine.disease, Phenotype, Sphingolipid, 030104 developmental biology, Child, Preschool, Microcephaly, Female, Psychomotor Disorders, business
Abstract: A woman with ichthyosis, contractures, and progressive neuropathy represents the first case of phosphoserine aminotransferase deficiency diagnosed and treated in an adult. She has novel compound heterozygous mutations in the gene PSAT1. Treatment with high dose oral L-serine completely resolved the ichthyosis. Consideration of this diagnosis is important because early treatment with L-serine repletion can halt progression of neurodegeneration and potentially improve neurological disabilities. As exome sequencing becomes more widely implemented in the diagnostic evaluation of progressive neurodegenerative phenotypes, adult neurologists and geneticists will increasingly encounter later onset manifestations of inborn errors of metabolism classically considered in infancy and early childhood.
Published: 2021
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16. Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases

Author: Shilpa Nadimpalli Kobren, Dustin Baldridge, Matt Velinder, Joel B. Krier, Kimberly LeBlanc, Cecilia Esteves, Barbara N. Pusey, Stephan Züchner, Elizabeth Blue, Hane Lee, Alden Huang, Lisa Bastarache, Anna Bican, Joy Cogan, Shruti Marwaha, Anna Alkelai, David R. Murdock, Pengfei Liu, Daniel J. Wegner, Alexander J. Paul, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennett, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Daya, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Grace L. LaMoure, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Brendan H. Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Calum A. MacRae, Ellen F. Macnamara, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martinez-Agosto, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Paolo Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stanley F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Aaron Quinlan, Archana N. Raja, Deepak A. Rao, Wendy Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, C. Ron Scott, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca H. Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, null Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, and Shamil R. Sunyaev
Subjects: Prioritization, Genome, medicine.diagnostic_test, Genomic sequencing, Multimodal data, Computational Biology, Structural variant, Genomics, Undiagnosed Diseases, Data science, Shruti, Article, Workflow, Biomedical data, medicine, Humans, Genetic Testing, Psychology, Software, Genetics (clinical), Genetic testing
Abstract: Author(s): Kobren, Shilpa Nadimpalli; Baldridge, Dustin; Velinder, Matt; Krier, Joel B; LeBlanc, Kimberly; Esteves, Cecilia; Pusey, Barbara N; Zuchner, Stephan; Blue, Elizabeth; Lee, Hane; Huang, Alden; Bastarache, Lisa; Bican, Anna; Cogan, Joy; Marwaha, Shruti; Alkelai, Anna; Murdock, David R; Liu, Pengfei; Wegner, Daniel J; Paul, Alexander J; Undiagnosed Diseases Network; Sunyaev, Shamil R; Kohane, Isaac S | Abstract: PurposeGenomic sequencing has become an increasingly powerful and relevant tool to be leveraged for the discovery of genetic aberrations underlying rare, Mendelian conditions. Although the computational tools incorporated into diagnostic workflows for this task are continually evolving and improving, we nevertheless sought to investigate commonalities across sequencing processing workflows to reveal consensus and standard practice tools and highlight exploratory analyses where technical and theoretical method improvements would be most impactful.MethodsWe collected details regarding the computational approaches used by a genetic testing laboratory and 11 clinical research sites in the United States participating in the Undiagnosed Diseases Network via meetings with bioinformaticians, online survey forms, and analyses of internal protocols.ResultsWe found that tools for processing genomic sequencing data can be grouped into four distinct categories. Whereas well-established practices exist for initial variant calling and quality control steps, there is substantial divergence across sites in later stages for variant prioritization and multimodal data integration, demonstrating a diversity of approaches for solving the most mysterious undiagnosed cases.ConclusionThe largest differences across diagnostic workflows suggest that advances in structural variant detection, noncoding variant interpretation, and integration of additional biomedical data may be especially promising for solving chronically undiagnosed cases.
Published: 2021
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17. Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy

Author: Yan Huang, May Christine V. Malicdan, Camilo Toro, William A. Gahl, Raman Sood, Paul G. Fisher, Gregory M. Enns, Shruti Marwaha, Edward P Frothingham, Abdel G. Elkahloun, Liliana Fernandez, Stephen B. Montgomery, Lynne A. Wolfe, Brian Harding, Elizabeth A. Burke, Thomas C. Markello, Diane B. Zastrow, Laure Fresard, Morgan L. Sturgeon, Kevin Bishop, Cameron J. Prybol, Alexander G. Bassuk, Patricia A. Ward, Christine M. Eng, Blake Carrington, and Matthew T. Wheeler
Subjects: 0301 basic medicine, Genetics, Protein family, KCTD7, Progressive myoclonus epilepsy, Biology, medicine.disease, biology.organism_classification, Compound heterozygosity, 03 medical and health sciences, Cellular and Molecular Neuroscience, Epilepsy, 030104 developmental biology, 0302 clinical medicine, medicine, medicine.symptom, Myoclonus, Zebrafish, 030217 neurology & neurosurgery, Exome sequencing
Abstract: KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.
Published: 2021
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18. Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science

Author: Kelly Schoch, Cecilia Esteves, Anna Bican, Rebecca Spillmann, Heidi Cope, Allyn McConkie-Rosell, Nicole Walley, Liliana Fernandez, Jennefer N. Kohler, Devon Bonner, Chloe Reuter, Nicholas Stong, John J. Mulvihill, Donna Novacic, Lynne Wolfe, Ayat Abdelbaki, Camilo Toro, Cyndi Tifft, May Malicdan, William Gahl, Pengfei Liu, John Newman, David B. Goldstein, Jason Hom, Jacinda Sampson, Matthew T. Wheeler, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J.Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Barbara N. Pusey, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J.Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C.Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Terra R. Coakley, Paul G. Fisher, Laure Fresard, Yong Huang, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, and Joy Cogan
Subjects: Exome sequencing, 0301 basic medicine, Computational biology, 030105 genetics & heredity, Genome sequencing, Article, DNA sequencing, Retrospective data, 03 medical and health sciences, Rare Diseases, Animals, Humans, Genomic medicine, Medicine, Medical diagnosis, Exome, Genetics (clinical), Retrospective Studies, Disease gene, business.industry, Genomics, 030104 developmental biology, Phenotyping, New disease, Undiagnosed diseases, Ultra-rare diseases, business
Abstract: Purpose The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices. Methods We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods. Results Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling. Conclusion Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.
Published: 2021
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19. Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)

Author: Frank Rutsch, Mary E. Hackbarth, Mary Scott Roberts, Rachel I Gafni, Margaret Whelpley, Michael A. Levine, Kristen S. Pan, William A. Gahl, Ellen Macnamara, Christina Jacobsen, Ingrid A. Holm, Carlos Ferreira, Sisi Wang, Esra Dikoglu, Timothy E Corden, M Zulf Mughal, Iris R Hartley, Douglas R. Rosing, Joy Bryant, Emily Y. Chew, Kerstin Müller, Marcus Y. Chen, and Shira G. Ziegler
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, ENPP1 Deficiency, Autosomal Recessive Hypophosphatemic Rickets type 2, Hearing loss, ABCC6, Rickets, 030105 genetics & heredity, Article, Generalized arterial calcification, Generalized Arterial Calcification of Infancy, 03 medical and health sciences, medicine, Pseudoxanthoma Elasticum, Genetics (clinical), biology, business.industry, Incidence (epidemiology), Pseudoxanthoma elasticum, medicine.disease, Hypophosphatemic Rickets, 030104 developmental biology, biology.protein, ABCC6 Deficiency, medicine.symptom, business, Calcification
Abstract: Purpose Generalized Arterial Calcification of Infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. Methods We performed deep phenotyping of 20 GACI survivors. Results Sixteen of twenty subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. Conclusions GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.
Published: 2021
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20. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease

Author: Sarthak Gupta, Amanda K. Ombrello, Emily Rominger, Megan Trick, Karyl S. Barron, Ryan S. Laird, Sinisa Savic, Shuichiro Nakabo, Daniela Ospina Cardona, Ivona Aksentijevich, Carmelo Carmona-Rivera, Gustaf Wigerblad, Mariana J. Kaplan, Emma M. Groarke, Laura W. Dillon, Chyi-Chia Richard Lee, Kalpana Manthiram, Kristina V. Wells, Nicholas Balanda, Zhijie Wu, Helen J. Lachmann, Daniel L. Kastner, Fernanda Gutierrez-Rodrigues, Achim Werner, Michele Nehrebecky, Lisha Xu, Alina Dulau-Florea, Wanxia L. Tsai, Bhavisha A Patel, Stefania Dell'Orso, Weixin Wang, Anthony J. Asmar, Danica Novacic, Katherine R. Calvo, David B. Beck, Robert A. Colbert, Massimo Gadina, William A. Gahl, Wendy Goodspeed, Natalie Deuitch, Dorota Rowczenio, Peter C. Grayson, Daron L. Ross, Sofia Rosenzweig, Anne Jones, Christopher S. Hourigan, James C. Mullikin, Stephen R. Brooks, Jason C. Collins, Wuhong Pei, May Christine V. Malicdan, Neal S. Young, Shawn M. Burgess, Keith A. Sikora, Mones Abu-Asab, Kyle Retterer, Patrycja Hoffmann, Hirotsugu Oda, Marcela A. Ferrada, Zuoming Deng, Benjamin D. Solomon, and Jae Jin Chae
Subjects: Genetics, Mutation, Somatic cell, business.industry, Sequence analysis, General Medicine, UBA1, 030204 cardiovascular system & hematology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Genotype, Medicine, Missense mutation, 030212 general & internal medicine, Age of onset, business, Gene
Abstract: Background Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may...
Published: 2020
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21. Skeletal Muscle Magnetic Resonance Biomarkers in GNE Myopathy

Author: Ronald M. Summers, William A. Gahl, Ronald Ouwerkerk, Chia-Ying Liu, Joseph A. Shrader, Jianhua Yao, Nuria Carrillo, Ami Mankodi, Galen O. Joe, and William Kovacs
Subjects: Adult, Male, Proton Magnetic Resonance Spectroscopy, Hamstring Muscles, Walk Test, Thigh, Severity of Illness Index, Article, Quadriceps Muscle, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Disease severity, Multienzyme Complexes, Humans, Medicine, Muscle Strength, Patient Reported Outcome Measures, 030212 general & internal medicine, Muscle, Skeletal, Myopathy, Aged, Leg, medicine.diagnostic_test, business.industry, Skeletal muscle, Magnetic resonance imaging, Organ Size, GNE MYOPATHY, Middle Aged, Lipid Metabolism, medicine.disease, Lipids, Magnetic Resonance Imaging, Hyperintensity, Distal Myopathies, medicine.anatomical_structure, Disease Progression, Female, Neurology (clinical), Inclusion body myositis, medicine.symptom, business, Nuclear medicine, 030217 neurology & neurosurgery
Abstract: ObjectiveTo characterize muscle involvement and evaluate disease severity in patients with GNE myopathy using skeletal muscle MRI and proton magnetic resonance spectroscopy (1H-MRS).MethodsSkeletal muscle imaging of the lower extremities was performed in 31 patients with genetically confirmed GNE myopathy, including T1-weighted and short tau inversion recovery (STIR) images, T1 and T2 mapping, and 1H-MRS. Measures evaluated included longitudinal relaxation time (T1), transverse relaxation time (T2), and 1H-MRS fat fraction (FF). Thigh muscle volume was correlated with relevant measures of strength, function, and patient-reported outcomes.ResultsThe cohort was representative of a wide range of disease progression. Contractile thigh muscle volume ranged from 5.51% to 62.95% and correlated with thigh strength (r = 0.91), the 6-minute walk test (r = 0.82), the adult myopathy assessment tool (r = 0.83), the activities-specific balance confidence scale (r = 0.65), and the inclusion body myositis functional rating scale (r = 0.62). Four stages of muscle involvement were distinguished by qualitative (T1W and STIR images) and quantitative methods: stage I: unaffected muscle (T1 = 1,033 ± 74.2 ms, T2 = 40.0 ± 1.9 ms, FF = 7.4 ± 3.5%); stage II: STIR hyperintense muscle with minimal or no fat infiltration (T1 = 1,305 ± 147 ms, T2 = 50.2 ± 3.5 ms, FF = 27.6 ± 12.7%); stage III: fat infiltration and STIR hyperintensity (T1 = 1,209 ± 348 ms, T2 = 73.3 ± 12.6 ms, FF = 57.5 ± 10.6%); and stage IV: complete fat replacement (T1 = 318 ± 39.9 ms, T2 = 114 ± 21.2 ms, FF = 85.6 ± 4.2%). 1H-MRS showed a significant decrease in intramyocellular lipid and trimethylamines between stage I and II, suggesting altered muscle metabolism at early stages.ConclusionMRI biomarkers can monitor muscle involvement and determine disease severity noninvasively in patients with GNE myopathy.ClinicalTrials.gov IdentifierNCT01417533.
Published: 2020
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22. NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity

Author: William A. Gahl, Elizabeth A. Burke, Yajun Tang, Melissa G. Dominguez, Ron A. Deckelbaum, May Christine V. Malicdan, Michael Podgorski, Brian Zambrowicz, James R. Lupski, Christopher J. Scheonherr, Wendy K. Chung, Dennis Delgado, Aris N. Economides, John Dronzek, Nicholas W. Gale, Richard A. Gibbs, Prasad Sarangapani, Samer Nuwayhid, Matthew C. Franklin, Harikiran Nistala, Shek Man Chim, Claudia Gonzaga-Jauregui, Saathyaki Rajamani, Ender Karaca, and Marjorie Withers
Subjects: 0301 basic medicine, AcademicSubjects/SCI01140, Male, Microcephaly, Biology, Compound heterozygosity, 03 medical and health sciences, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, Genetics, medicine, Missense mutation, Animals, Humans, Global developmental delay, Allele, Molecular Biology, Genetics (clinical), Alleles, Infant, Heterozygote advantage, General Medicine, medicine.disease, Hypotonia, Phosphoric Monoester Hydrolases, Acid Anhydride Hydrolases, Pedigree, 030104 developmental biology, Phenotype, Neurodevelopmental Disorders, Child, Preschool, Mutation, Muscle Hypotonia, Female, General Article, medicine.symptom, 030217 neurology & neurosurgery
Abstract: Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.
Published: 2020

23. Prospective evaluation of kidney and liver disease in autosomal recessive polycystic kidney disease-congenital hepatic fibrosis

Author: Meral Gunay-Aygun, Nehna Abdul Majeed, Linda Lukose, Theo Heller, Joy Bryant, Esperanza Font-Montgomery, Peter L. Choyke, Peter Veppumthara, Ismail B. Turkbey, and William A. Gahl
Subjects: Adult, Liver Cirrhosis, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Receptors, Cell Surface, 030105 genetics & heredity, Liver transplantation, Kidney, Compound heterozygosity, Biochemistry, Gastroenterology, Article, Cohort Studies, Young Adult, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Endocrinology, Internal medicine, Hypertension, Portal, Genetics, medicine, Humans, Prospective Studies, Child, Molecular Biology, Kidney transplantation, Polycystic Kidney, Autosomal Recessive, business.industry, Genetic Diseases, Inborn, medicine.disease, Kidney Transplantation, Autosomal Recessive Polycystic Kidney Disease, Liver Transplantation, Cross-Sectional Studies, medicine.anatomical_structure, Liver, Disease Progression, Portal hypertension, Congenital hepatic fibrosis, Female, business, 030217 neurology & neurosurgery
Abstract: Background and objectives We have previously published the characteristics of kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic kidney disease-congenital hepatic fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort. Design, setting, participants, and measurements Comprehensive biochemical and imaging data on progression of kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019. Results and conclusions Of the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was −1.6 ml/min/1.73 m2/y, in comparison to −0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney size remained the same over time and normalized to the upper limit of normal by 20–25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the “medullary” to the “corticomedullary” group. There was no correlation between eGFR slope and kidney size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.
Published: 2020
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24. Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder

Author: Katherine Wesseling Perry, Archana Raja, Emilie D. Douine, Xue Zhong Liu, Brent L. Fogel, Stan F. Nelson, Kenneth R. Maravilla, Eva H. Baker, Dave Viskochil, Kerstin Kutsche, Jordan H. Whitlock, Susan L. Samson, Christine M. Eng, Chloe M. Reuter, Suman Jayadev, David R. Adams, Sihoun Hahn, Rebecca C. Spillmann, Margaret Adam, Heather C Mefford, John C. Carey, Ehsan Ghayoor Karimiani, Donna M. Krasnewich, David Goldstein, Susan A. Korrick, Guoyun Yu, Tomas Honzik, Henry Houlden, Andrea L. Gropman, David A. Sweetser, Anna Bican, Carlos A. Bacino, Liliana Fernandez, Gabrielle Brown, Justin Alvey, Hane Lee, Emanuele G. Coci, Hongzheng Dai, Mario Saporta, Laurel A. Cobban, John F. Bohnsack, Stephanie Fox, Heidi Cope, Tyra Estwick, Lorraine Potocki, Nichole Hayes, Elizabeth A. Burke, Rizwan Hamid, Aaron R. Quinlan, Kelly Hassey, Lindsay C. Burrage, Jane Juusola, Adeline Vanderver, Malik Alawi, Teri A. Manolio, Maja Hempel, Esther M. Maier, Jennifer Kennedy, Bruce D. Gelb, Martha Horike-Pyne, Amarilis Sanchez-Valle, Euan A. Ashley, Surendra Dasari, Elizabeth Blue, Eva Morava-Kozicz, Natalie Rosenwasser, Alan H. Beggs, Bryn D. Webb, Isaac S. Kohane, Kelly Schoch, C. Christopher Lau, Nicole M. Walley, Laura M. Amendola, Genecee Renteria, Catherine H. Sillari, Jonathan A. Bernstein, Pinar Bayrak-Toydemir, R. Frank Kooy, Mariko Nakano-Okuno, Manuela Siekmeyer, Marije E. C. Meuwissen, Stephanie Bivona, Mark Wener, Precilla D'Souza, Olveen Carrasquillo, Paolo Moretti, Diane B. Zastrow, David J. Eckstein, Janet S. Sinsheimer, Kathy Sisco, Holly K. Tabor, William E. Byrd, Esteban C. Dell'Angelica, Rosario Isasi, Jacinda B. Sampson, Carsten Bonnenmann, J. Lawrence Merritt, Joan M. Stoler, Richard L. Maas, Paul G. Fisher, Jeanette C. Papp, Kimberly LeBlanc, Lilianna Solnica-Krezel, Mustafa Tekin, Mathias Woidy, Andrew B. Crouse, Katleen Ballon, David Murphy, Matthew T. Wheeler, Joseph Loscalzo, Ellen Macnamara, Cecelia P. Tamburro, Lefkothea P. Karaviti, Chunli Zhao, Ingrid A. Holm, Pankaj B. Agrawal, Alana L. Grajewski, Stephen C. Pak, Ian R. Lanza, Mohammad Doosti, Jennifer E. Posey, Rebecca Signer, Katie Golden-Grant, Christopher A. Walsh, Alica M. Goldman, Jyoti G. Dayal, Queenie K.-G. Tan, Martin G. Martin, Joy D. Cogan, Kevin S. Smith, Deborah A. Nickerson, Elisabeth McGee, Laure Fresard, Rena A. Godfrey, Sharyn A. Lincoln, Kathleen E. Sullivan, Mariska Davids, Melissa A. Walker, Prashant Sharma, Maria Iascone, Neil H. Parker, Carlos Ferreira, Elizabeth L. Fieg, Edwin K. Silverman, Michael L. Cunningham, Pengfei Liu, Edward M. Behrens, Sandra K. Loo, David R. Murdock, F. Sessions Cole, C. Ron Scott, Dan Doherty, Elly Brokamp, John H. Newman, Alden Y. Huang, Laura A. Pace, Avi Nath, Jimmy Bennet, Georg Christoph Korenke, Alyssa A. Tran, Gabriel F. Batzli, Jimann Shin, Matthew A. Deardorff, Naghmeh Dorrani, Diane Beysen, Irma Gutierrez, Stanislav Kmoch, Majid Alfadhel, Fred F. Telischi, Jennifer A. Sullivan, William A. Gahl, María Palomares-Bralo, Gerard T. Berry, Colleen E. McCormack, Lance H. Rodan, Reza Maroofian, Lenka Nosková, Judy Schaechter, Lynne A. Wolfe, Deborah Krakow, Daryl A. Scott, Tara Wenger, Jason Hom, Dustin Baldridge, Lynette Rives, Lee-kai Wang, Dawn L. Earl, Ralph L. Sacco, Fernando Santos-Simarro, Irman Forghani, Fuki M. Hisama, Terra R. Coakley, Hsiao-Tuan Chao, Jeremy D. Woods, Emily G. Kelley, Jean M. Johnston, Neil A. Hanchard, Amy K. Robertson, Matt Velinder, Byron L. Lam, Wendy H. Raskind, William J. Craigen, Stephan Züchner, Guney Bademci, Julian A. Martinez-Agosto, Mary Koziura, Beth A. Martin, Angela Sun, John A. Phillips, Seema R. Lalani, Daniela Buhas, Emily Solem, Gary D. Clark, Gill Bejerano, Ingo Kurth, Deborah Barbouth, Tiina K. Urv, Fanny Kortüm, Ian A. Glass, Ta Chen Peter Chang, Yong Huang, Roy C. Levitt, Paola Francesca Ajmone, Brenna Boyd, René Santer, Tim Schedl, David D. Draper, Ghayda M. Mirzaa, Aroa Rodríguez Alonso, Stephanie Wallace, Colleen E. Wahl, Calum A. MacRae, Gail P. Jarvik, Jacob L. McCauley, Jill A. Rosenfeld, Ronit Marom, Monte Westerfield, Matthew Might, Poupak Javaher-Haghighi, Brendan C. Lanpher, Devon Bonner, Cynthia J. Tifft, Cecilia Esteves, May Christine V. Malicdan, Jim Bale, Fariha Jamal, Nicola Longo, Christina G.S. Palmer, Lisa Emrick, Peter H. Byers, Vandana Shashi, Tiphanie P. Vogel, Richard A. Lewis, Jijun Wan, Barbara N. Pusey, Maria T. Acosta, Jaak Jaeken, Allyn McConkie-Rosell, Shirley Sutton, John Yang, Lorenzo D. Botto, Hilde Peeters, Rong Mao, Catherine Groden, Brendan Lee, Marta M. Majcherska, Rami Abou Jamra, Ashok Balasubramanyam, Joel B. Krier, Majid Mojarrad, Maria Francesca Bedeschi, Mahshid S. Azamian, Shruti Marwaha, Heather A. Colley, Katrina M. Dipple, Sirisak Chanprasert, Alexa T. McCray, Nicholas Stong, Anne V. Hing, Laura A. Mamounas, Edward C. Smith, Lauren C. Briere, John J.E. Mulvihill, Virginia P. Sybert, Maura R.Z. Ruzhnikov, Valerie Maduro, Frances A. High, Manish J. Butte, Willa Thorson, J. Carl Pallais, Jennefer N. Kohler, Dana Kiley, Raphael Bernier, Christina Lam, Michael J. Bamshad, Patricia A. Ward, Michael F. Wangler, Anita E. Beck, Shinya Yamamoto, Beverly Berg-Rood, Robb Rowley, Gabor T. Marth, Cynthia M. Cooper, Jeffrey G. Jarvik, Thomas C. Markello, Saskia Biskup, Devin Oglesbee, Laura Duncan, Elijah Kravets, Daniel J. Wegner, Mercedes E. Alejandro, Sarah K. Nicholas, Jennifer A. Wambach, Marni J. Falk, Brianna M. Tucker, Marie Morimoto, Corina Heller, Donna Novacic, Camilo Toro, Ashley Andrews, James P. Orengo, Shweta U. Dhar, and Pauline E. Schneeberger
Subjects: 0301 basic medicine, MAPK/ERK pathway, Death Domain Receptor Signaling Adaptor Proteins, Programmed cell death, Developmental Disabilities, Biology, 03 medical and health sciences, 0302 clinical medicine, Epidermal growth factor, medicine, Guanine Nucleotide Exchange Factors, Humans, Death domain, Kinase, Original Articles, Phenotype, Hypotonia, Protein Transport, 030104 developmental biology, Mutation, Cancer research, Human medicine, Neurology (clinical), Nervous System Diseases, Signal transduction, medicine.symptom, 030217 neurology & neurosurgery, Signal Transduction
Abstract: In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.
Published: 2020
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25. Aortic distensibility in alkaptonuria

Author: Wendy J. Introne, Kevin J. O'Brien, Jeannie H. Yu, Marcus Y. Chen, Sujata M Shanbhag, Rashmi Thimmapuram, W. Patricia Bandettini, and William A. Gahl
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Cardiovascular health, Aorta, Thoracic, 030105 genetics & heredity, Alkaptonuria, Biochemistry, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Internal medicine, medicine.artery, Hyperlipidemia, Genetics, medicine, Humans, Thoracic aorta, Homogentisic acid, Vascular Calcification, Molecular Biology, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, Middle Aged, Prognosis, medicine.disease, chemistry, Case-Control Studies, Coronary artery calcification, cardiovascular system, Cardiology, Female, Aortic stiffness, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Introduction Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism resulting in an accumulation of homogentisic acid oxidation products in the joints and cardiovascular system. Aortic distensibility may be a non-invasive indicator of cardiovascular complications. Descending thoracic aortic distensibility in alkaptonuria has not been studied. Methods Patients diagnosed with alkaptonuria underwent Magnetic Resonance Imaging (MRI) and gated non-contrast and contrast-enhanced cardiovascular computed tomography. Using MRI cine images, aortic distensibility of the descending thoracic aorta was determined. Results Seventy-six patients with alkaptonuria were imaged. When compared to literature normal values, aortic distensibility in AKU was impaired (5.2 vs 6.2 × 10−3, p Conclusions Patients with alkaptonuria have impaired aortic distensibility, which is likely an early marker for reduced cardiovascular health. Variables such as age, hypertension, hyperlipidemia, and aortic and coronary calcification were associated with impaired distensibility.
Published: 2020
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26. Nephropathic Cystinosis: A Distinct Form of CKD–Mineral and Bone Disorder that Provides Novel Insights into the Regulation of FGF23

Author: Rachel I Gafni, William A. Gahl, Macarena Jiménez, Harald Jüppner, Myles Wolf, Galina Nesterova, Barbara Gales, Luis F de Castro, Michael T. Collins, Isidro B. Salusky, Mary Scott Roberts, Pablo Florenzano, Carlos Ferreira, Sri Harsha Tella, Katherine Wesseling-Perry, and Daniela Markovich
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Urinary system, Cystinosis, Disease, urologic and male genital diseases, Gastroenterology, Phosphates, Young Adult, Clinical Research, Chronic kidney disease-mineral and bone disorder, Nephropathic Cystinosis, Internal medicine, Lysosomal storage disease, Homeostasis, Humans, Medicine, Vitamin D, Child, Wasting, Chronic Kidney Disease-Mineral and Bone Disorder, business.industry, Fanconi syndrome, General Medicine, medicine.disease, female genital diseases and pregnancy complications, Fibroblast Growth Factors, Fibroblast Growth Factor-23, Nephrology, Child, Preschool, Renal physiology, Female, medicine.symptom, business
Abstract: Background The rare lysosomal storage disease nephropathic cystinosis presents with renal Fanconi syndrome that evolves in time to CKD. Although biochemical abnormalities in common causes of CKD-mineral and bone disorder have been defined, it is unknown if persistent phosphate wasting in nephropathic cystinosis is associated with a biochemical mineral pattern distinct from that typically observed in CKD-mineral and bone disorder. Methods We assessed and compared determinants of mineral homeostasis in patients with nephropathic cystinosis across the predialysis CKD spectrum to these determinants in age- and CKD stage-matched patients, with causes of CKD other than nephropathic cystinosis. Results The study included 50 patients with nephropathic cystinosis-related CDK and 97 with CKD from other causes. All major aspects of mineral homeostasis were differentially effected in patients with CKD stemming from nephropathic cystinosis versus other causes. Patients with nephropathic cystinosis had significantly lower percent tubular reabsorption of phosphate and fibroblast growth factor-23 (FGF23) at all CKD stages, and lower blood phosphate in CKD stages 3-5. Linear regression analyses demonstrated lower FGF23 levels in nephropathic cystinosis participants at all CKD stages when corrected for eGFR and age, but not when adjusted for serum phosphate. Conclusions Nephropathic cystinosis CKD patients have mineral abnormalities that are distinct from those in CKD stemming from other causes. Persistently increased urinary phosphate excretion maintains serum phosphate levels within the normal range, thus protecting patients with nephropathic cystinosis from elevations of FGF23 during early CKD stages. These findings support the notion that phosphate is a significant driver of increased FGF23 levels in CKD and that mineral abnormalities associated with CKD are likely to vary depending on the underlying renal disease.
Published: 2020
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27. Mutations in <scp>GET4</scp> disrupt the transmembrane domain recognition complex pathway

Author: Shino Shimada, Bobby G. Ng, May Malicdan, David R. Adams, Deborah A. Nickerson, William A. Gahl, Michael J. Bamshad, Lynne A. Wolfe, Hudson H. Freeze, and Mitali A. Tambe
Subjects: Male, Models, Molecular, Golgi Apparatus, Mitochondrion, Endoplasmic Reticulum, medicine.disease_cause, Article, 03 medical and health sciences, symbols.namesake, Congenital Disorders of Glycosylation, Protein targeting, Genetics, medicine, Humans, Syntaxin, Child, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Chemistry, Endoplasmic reticulum, 030305 genetics & heredity, Golgi apparatus, Cell biology, Protein Transport, Transmembrane domain, Cytoplasm, Mutation, Proteasome inhibitor, symbols, Molecular Chaperones, Signal Transduction, medicine.drug
Abstract: The transmembrane domain recognition complex (TRC) targets cytoplasmic C-terminal tail-anchored (TA) proteins to their respective membranes in the endoplasmic reticulum (ER), Golgi, and mitochondria. It is composed of three proteins, GET4, BAG6, and GET5. We identified an individual with compound heterozygous missense variants (p.Arg122His, p.Ile279Met) in GET4 that reduced all three TRC proteins by 70% to 90% in his fibroblasts, suggesting a possible defect in TA protein targeting. He presented with global developmental delay, intellectual disabilities, seizures, facial dysmorphism, and delayed bone age. We found the TA protein, syntaxin 5, is poorly targeted to Golgi membranes compared to normal controls. Since GET4 regulates ER to Golgi transport, we hypothesized that such transport would be disrupted in his fibroblasts, and discovered that retrograde (but not anterograde) transport was significantly reduced. Despite reduction in the three TRC proteins, their mRNA levels were unchanged, suggesting increased degradation in patient fibroblasts. Treating fibroblasts with the FDA-approved proteasome inhibitor, bortezomib (10 nM), restored syntaxin 5 localization and nearly normalized the levels of all three TRC proteins. Our study identifies the first individual with GET4 mutations.
Published: 2020
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28. De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation

Author: Dongxue Mao, Chloe M. Reuter, Maura R.Z. Ruzhnikov, Anita E. Beck, Emily G. Farrow, Lisa T. Emrick, Jill A. Rosenfeld, Katherine M. Mackenzie, Laurie Robak, Matthew T. Wheeler, Lindsay C. Burrage, Mahim Jain, Pengfei Liu, Daniel Calame, Sébastien Küry, Martin Sillesen, Klaus Schmitz-Abe, Davide Tonduti, Luigina Spaccini, Maria Iascone, Casie A. Genetti, Mary K. Koenig, Madeline Graf, Alyssa Tran, Mercedes Alejandro, Brendan H. Lee, Isabelle Thiffault, Pankaj B. Agrawal, Jonathan A. Bernstein, Hugo J. Bellen, Hsiao-Tuan Chao, Maria T. Acosta, Margaret Adam, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Raphael Bernier, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Elizabeth A. Burke, Manish J. Butte, Peter Byers, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Yong-hui Jiang, Jean M. Johnston, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Kimberly LeBlanc, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Genecee Renteria, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: Male, 0301 basic medicine, Proband, Ataxia, Adolescent, Developmental Disabilities, Nervous System Malformations, Leukoencephalopathy, eIF-2 Kinase, 03 medical and health sciences, 0302 clinical medicine, Leukoencephalopathies, Report, Genetics, medicine, Humans, Missense mutation, Kinase activity, Child, Genetics (clinical), biology, Leukodystrophy, Genetic Variation, Infant, medicine.disease, White Matter, Hypotonia, Hereditary Central Nervous System Demyelinating Diseases, 030104 developmental biology, Child, Preschool, eIF2B, Immunology, biology.protein, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract: EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.
Published: 2020
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29. Neurological manifestations of Erdheim–Chester Disease

Author: Juvianee Estrada-Veras, Kevin J. O'Brien, Louisa C. Boyd, Camilo Toro, Bernadette R. Gochuico, Neval Ozkaya, Fady Hannah-Shmouni, Avindra Nath, Rahul Dave, Tanya J. Lehky, Avner Meoded, and William A. Gahl
Subjects: 0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Erdheim-Chester Disease, genetic structures, Cerebellar Ataxia, Neurosciences. Biological psychiatry. Neuropsychiatry, White matter, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Atrophy, medicine, Humans, Cognitive Dysfunction, Prospective Studies, RC346-429, Histiocyte, Research Articles, Aged, Cerebral atrophy, Cerebellar ataxia, business.industry, General Neuroscience, Peripheral Nervous System Diseases, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Histiocytosis, 030104 developmental biology, medicine.anatomical_structure, Peripheral neuropathy, Erdheim–Chester disease, Female, Neurology (clinical), Neurology. Diseases of the nervous system, medicine.symptom, Nervous System Diseases, business, 030217 neurology & neurosurgery, RC321-571, Research Article
Abstract: Objective To characterize the spectrum of neurologic involvement in Erdheim–Chester Disease (ECD), a treatable inflammatory neoplasm of histiocytes. Methods Sixty‐two patients with ECD were prospectively enrolled in a natural history study that facilitated collection of clinical, imaging, laboratory, neurophysiologic, and pathologic data. Results Ninety‐four percent of the patients had neurologic abnormalities on examination or imaging, and 22% had neurologic symptoms as the initial presentation of ECD. The most common neurologic findings were cognitive impairment, peripheral neuropathy, pyramidal tract signs, cranial nerve involvement, and cerebellar ataxia. Imaging revealed atrophy and demyelination along with focal lesions that were located throughout the nervous system, dura, and extra‐axial structures. The BRAF V600E variant correlated with cerebral atrophy. Brain pathology revealed lipid‐laden, phagocytic macrophages (histiocytes) accompanied by demyelination and axonal degeneration. Interpretation In patients with ECD, neurologic morbidity is common and contributes significantly to disability. Since neurologic symptoms can be the presenting feature of ECD and, given the mean delay in ECD diagnosis is 4.2 years, it is critical that neurologists consider of ECD and other histiocytosis in patients with inflammatory, infectious, or neoplastic‐appearing white matter. Furthermore, given the broad spectrum of neurologic involvement, neurologists have an important role in a team of specialists treating ECD patients.
Published: 2020

30. Bleomycin Induces Drug Efflux in Lungs. A Pitfall for Pharmacological Studies of Pulmonary Fibrosis

Author: Nathan J. Coffey, Lindsey Jay, Joshua K. Park, Resat Cinar, Steven P. Bodine, Charles N. Zawatsky, William A. Gahl, May Christine V. Malicdan, George Kunos, and Bernadette R. Gochuico
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Abcg2, medicine.medical_treatment, Clinical Biochemistry, ATP-binding cassette transporter, Drug resistance, Pharmacology, Bleomycin, 03 medical and health sciences, chemistry.chemical_compound, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Pulmonary fibrosis, medicine, Lung transplantation, Molecular Biology, biology, business.industry, Cell Biology, respiratory system, medicine.disease, respiratory tract diseases, 030104 developmental biology, 030228 respiratory system, chemistry, biology.protein, Nintedanib, business
Abstract: ATP-binding cassette (ABC) transporters are evolutionarily conserved membrane proteins that pump a variety of endogenous substrates across cell membranes. Certain subfamilies are known to interact with pharmaceutical compounds, potentially influencing drug delivery and treatment efficacy. However, the role of drug resistance-associated ABC transporters has not been examined in idiopathic pulmonary fibrosis (IPF) or its animal model: the bleomycin (BLM)-induced murine model. Here, we investigate the expression of two ABC transporters, P-gp (permeability glycoprotein) and BCRP (breast cancer resistance protein), in human IPF lung tissue and two different BLM-induced mouse models of pulmonary fibrosis. We obtained human IPF specimens from patients during lung transplantation and administered BLM to male C57BL/6J mice either by oropharyngeal aspiration (1 U/kg) or subcutaneous osmotic infusion (100 U/kg over 7 d). We report that P-gp and BCRP expression in lungs of patients with IPF was comparable to controls. However, murine lungs expressed increased levels of P-gp and BCRP after oropharyngeal and subcutaneous BLM administration. We localized this upregulation to multiple pulmonary cell types, including alveolar fibroblasts, endothelial cells, and type 2 epithelial cells. Functionally, this effect reduced murine lung exposure to nintedanib, a U.S. Food and Drug Administration-approved IPF therapy known to be a P-gp substrate. The study reveals a discrepancy between IPF pathophysiology and the common animal model of lung fibrosis. BLM-induced drug efflux in the murine lungs may present an uncontrolled confounding variable in the preclinical study of IPF drug candidates, and these findings will facilitate disease model validation and enhance new drug discoveries that will ultimately improve patient outcomes.
Published: 2020
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31. CB1R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky–Pudlak syndrome

Author: George Kunos, Lindsey Jay, Charles N. Zawatsky, Resat Cinar, Ken Mackie, Joshua K. Park, Bernadette R. Gochuico, Mei Xing G. Zuo, Asaf Alimardanov, Steven P. Bodine, Tadafumi Yokoyama, Junfeng Huang, Nathan J. Coffey, Kevin J. O'Brien, William A. Gahl, May Christine V. Malicdan, Tony Jourdan, Malliga R. Iyer, and Jasmina Abdalla
Subjects: Male, Medicine (General), lung disease, Cannabinoid receptor, Pulmonary Fibrosis, Medicine (miscellaneous), Nitric Oxide Synthase Type II, Pharmacology, Pulmonary function testing, Receptor, Cannabinoid, CB1, Fibrosis, Pulmonary fibrosis, Lung, Research Articles, medicine.diagnostic_test, biology, Middle Aged, respiratory system, Interleukin-11, Endocannabinoid system, Nitric oxide synthase, medicine.anatomical_structure, Hermanski-Pudlak Syndrome, Molecular Medicine, Female, Antifibrotic Agents, Bronchoalveolar Lavage Fluid, Research Article, Adult, Polyunsaturated Alkamides, rare disease, Arachidonic Acids, Transforming Growth Factor beta1, Bleomycin, R5-920, medicine, Animals, Humans, endocannabinoids, polypharmacology, business.industry, fibrosis, Fibroblasts, medicine.disease, respiratory tract diseases, Mice, Inbred C57BL, Disease Models, Animal, Bronchoalveolar lavage, biology.protein, business
Abstract: Hermansky–Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS‐1, leads to fatal adult‐onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB1R system and inducible nitric oxide synthase (iNOS) for dual‐target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS‐PF patient‐derived lung fibroblasts, and bleomycin‐induced PF in pale ear mice (HPS1ep/ep). We found overexpression of CB1R and iNOS in fibrotic lungs of HPSPF patients and bleomycin‐infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin‐induced PF. Simultaneous targeting of CB1R and iNOS by MRI‐1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI‐1867 treatment abrogated bleomycin‐induced increases in lung levels of the profibrotic interleukin‐11 via iNOS inhibition and reversed mitochondrial dysfunction via CB1R inhibition. Dual inhibition of CB1R and iNOS is an effective antifibrotic strategy for HPSPF., Overactivity of CB1R and iNOS contributes to HPSPF development and progression via multiple critical pathological processes including dysregulation of mitochondrial function and IL‐11. Simultaneous inhibition of lung CB1R and iNOS by a hybrid inhibitor (MRI‐1867) is a rational therapeutic strategy for achieving therapeutic efficacy in HPSPF with attenuating fibrosis, improving pulmonary function and survival.
Published: 2021

32. A call for global action for rare diseases in Africa

Author: Ann Nordgren, Stephanie Broley, Mengchun Gong, James Chipeta, Zhang Shuyang, Durhane Wong-Rieger, Stephen C. Groft, Benjamin Djoudalbaye, Kristen J. Nowak, Maja Stojiljkovic, Kenjiro Kosaki, William A. Gahl, Safiyya D. Gassman, Maximilian Muenke, Sarah Bowdin, Emily P. Coles, David R. Adams, Judit Kumuthini, Manuel Posada, Tebogo Selebatso, Christopher P. Austin, Annika Larsson, Moses Selebatso, Eda Selebatso, Ruty Mehrian-Shai, Ratna D. Puri, Helene Cederroth, Christoffer Nellåker, Barbara Wuebbels, Gareth Baynam, Virginia A. Llera, Domenica Taruscio, Simon Easteal, Juergen K. V. Reichardt, Nicholas Pachter, Sergi Beltran, Maryke Schoonen, Dipesalema Joel, Feng Zhang, Francois H. van der Westhuizen, Barend Christiaan Vorster, Kelly du Plessis, Désirée Gavhed, Kym M. Boycott, Emilio J. A. Roldán, Petra Kaufmann, John Forman, Gemma A. Bilkey, Boikobo Gaobinelwe, Clara D.M. van Karnebeek, AGEM - Inborn errors of metabolism, Paediatric Metabolic Diseases, 10213503 - Van der Westhuizen, Francois Hendrikus, and 22713077 - Vorster, Barend Christiaan
Subjects: medicine.medical_specialty, International Cooperation, education, MEDLINE, Health Promotion, Biology, Global Health, Orphan drug, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Genetics, Global health, medicine, Humans, Health planning, health care economics and organizations, 030304 developmental biology, 0303 health sciences, business.industry, Public health, Public relations, Call to action, Health Planning, Health promotion, Action (philosophy), Africa, business, 030217 neurology & neurosurgery
Abstract: The 11th International Conference on Rare Diseases and Orphan Drugs (ICORD), South Africa, included the Africa-Rare initiative launch and facilitated multi-stakeholder engagement in the challenges facing, and opportunities for, Africans living with rare diseases. The following ICORD Global Call to Action, developed in collaboration with the International Rare Diseases Research Consortium, synthesizes the outcomes of the deliberations and emphasizes the international collaborative efforts required to address the global effects of rare diseases on public health.
Published: 2019
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33. Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

Author: Musa Karakukcu, Ratnadeep Mukherjee, Lynne A. Wolfe, Aaron Morawski, Lixin Zheng, Niraj C. Patel, Samuel D. Chauvin, Helen F. Matthews, Brian Sellers, Julio C. Orrego-Arango, Tingyan He, Susan Price, Alexandre G. R. Day, Pankaj Mehta, Les R. Folio, Giulia Notarangelo, Jordan S. Orange, James T. Anibal, Evan M. Masutani, Pam Angelus, Chrysi Kanellopoulou, Claudia M. Trujillo-Vargas, Sally Hunsberger, David E. Kleiner, Suk See De Ravin, Jenna R.E. Bergerson, Michael J. Lenardo, Devika Kapuria, Matthew Biancalana, Gulbu Uzel, Mami Matsuda-Lennikov, Sebastian Gutierrez-Hincapie, Alex George, Camilo Toro, Jeffrey I. Cohen, Juan Zou, Ivan K. Chinn, Juan C. Ravell, Ping Jiang, Harry L. Malech, William A. Gahl, Ekrem Unal, Grégoire Altan-Bonnet, Matthias Mann, Kyle Binder, Turkan Patiroglu, Stefania Pittaluga, Astin Powers, Helen C. Su, Kimiyo Raymond, Marc G. Ghany, Sally J. Deeb, José Luis Franco, and V. Koneti Rao
Subjects: Male, 0301 basic medicine, Glycosylation, Lymphoma, Immunology, XMEN disease, Naive B cell, CD4-CD8 Ratio, Glycobiology, CD38, X-Linked Combined Immunodeficiency Diseases, Autoimmune Disease, Medical and Health Sciences, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Antigens, CD, Clinical Research, immune system diseases, hemic and lymphatic diseases, medicine, Humans, 2.1 Biological and endogenous factors, Antigens, Aetiology, Dysgammaglobulinemia, Cation Transport Proteins, B cell, Immunodeficiency, Cancer, business.industry, Autoimmune Lymphoproliferative Syndrome, Hematology, General Medicine, medicine.disease, NKG2D, CD, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Commentary, Female, Proteoglycans, business, Magnesium Deficiency, Congenital disorder of glycosylation, Genetic diseases
Abstract: X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.
Published: 2019
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34. Magnetic Resonance Imaging characteristics in case of TOR1AIP1 muscular dystrophy

Author: Aashim Bhatia, Bret C. Mobley, Joy Cogan, Mary E. Koziura, Elly Brokamp, John Phillips, John Newman, Steven A. Moore, Rizwan Hamid, Maria T. Acosta, David R. Adams, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Alan H. Beggs, Gill Bejerano, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lorenzo Botto, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Neil A. Hanchard, Nichole Hayes, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Sandra K. Loo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Shirley Sutton, David A. Sweetser, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: medicine.medical_specialty, Adolescent, Gene mutation, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Muscular dystrophy, Muscle, Skeletal, Gluteal muscles, Muscle Weakness, Muscle biopsy, medicine.diagnostic_test, business.industry, Muscle weakness, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Muscular Atrophy, medicine.anatomical_structure, Lower Extremity, Muscular Dystrophies, Limb-Girdle, 030220 oncology & carcinogenesis, Female, Radiology, Iliopsoas, medicine.symptom, business, Molecular Chaperones
Abstract: Mutations in the torsinA-interacting protein 1 (TOR1AIP1) gene result in a severe muscular dystrophy with minimal literature in the pediatric population. We review a case of TOR1AIP1 gene mutation in a 16-year-old Caucasian female with a long history of muscle weakness. Extensive clinical workup was performed and MRI at time of initial presentation demonstrated no significant muscular atrophy with heterogenous STIR hyperintensity of the lower extremity muscles. MRI findings seven years later included extensive atrophy of the lower extremities, with severe progression, including the gluteal muscles, iliopsoas, rectus femoris, and obturator internus. There was also significant atrophy of the rectus abdominis and internal and external oblique muscles, and iliacus muscles. The MRI findings showed more proximal involvement of lower extremities and no atrophy of the tibialis anterior, making TOR1AIP1 the more likely genetic cause. Muscle biopsy findings supported TOR1AIP1 limb-girdle muscular dystrophy. Though rare, TOR1AIP1 gene mutation occurs in pediatric patients and MRI can aid in diagnosis and help differentiate from other types of muscular dystrophy. Genetic and pathology workup is also crucial to accurate diagnosis and possible treatment of these patients.
Published: 2019
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35. Cerebral and portal vein thrombosis, macrocephaly and atypical absence seizures in Glycosylphosphatidyl inositol deficiency due to a PIGM promoter mutation

Author: Carlos Ferreira, Amit Mary Philosoph, Assaf Arie Barg, Dror S. Shouval, Helly Vernitsky, Ben Pode-Shakked, Gali Heimer, Dana Levinkopf, Gili Kenet, William A. Gahl, Yair Anikster, Mariska Davids, Dina Marek-Yagel, Thierry Vilboux, Ninette Amariglio, Avishay Lahad, Marina Safaniev, Michalle Soudack, Chen Hoffmann, Maya Lodzki, Bruria Ben-Zeev, May Christine V. Malicdan, Naomi Pode-Shakked, Alvit Veber, Ayman Daka, and Batia Weiss
Subjects: Male, 0301 basic medicine, Adolescent, Glycosylphosphatidylinositols, Endocrinology, Diabetes and Metabolism, Atypical absence seizures, Prenatal diagnosis, Disease, 030105 genetics & heredity, medicine.disease_cause, Bioinformatics, Mannosyltransferases, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Seizures, Genetics, medicine, Humans, Child, Promoter Regions, Genetic, Molecular Biology, Mutation, Portal Vein, business.industry, Macrocephaly, Infant, Thrombosis, Sodium phenylbutyrate, medicine.disease, Magnetic Resonance Imaging, Phenotype, Megalencephaly, Portal vein thrombosis, Child, Preschool, Female, medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Defects of the glycosylphosphatidylinositol (GPI) biosynthesis pathway constitute an emerging subgroup of congenital disorders of glycosylation with heterogeneous phenotypes. A mutation in the promoter of PIGM, resulting in a syndrome with portal vein thrombosis and persistent absence seizures, was previously described in three patients. We now report four additional patients in two unrelated families, with further clinical, biochemical and molecular delineation of this unique entity. We also describe the first prenatal diagnosis of PIGM deficiency, allowing characterization of the natural history of the disease from birth. The patients described herein expand the phenotypic spectrum of PIGM deficiency to include macrocephaly and infantile-onset cerebrovascular thrombotic events. Finally, we offer insights regarding targeted treatment of this rare disorder with sodium phenylbutyrate.
Published: 2019
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36. Maternal ornithine transcarbamylase deficiency, a genetic condition associated with high maternal and neonatal mortality every clinician should know: A systematic review

Author: Mehnoosh Torkzaban, Andrew Haddad, Huda B. Al-Kouatly, Vincenzo Berghella, Jason K. Baxter, and William A. Gahl
Subjects: Adult, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Urea cycle disorder, medicine.medical_treatment, 030105 genetics & heredity, 03 medical and health sciences, Hyperemesis gravidarum, Pregnancy, Infant Mortality, Genetics, medicine, Humans, Genetics (clinical), Ornithine transcarbamylase deficiency, Dialysis, Coma, business.industry, Postpartum Period, Infant, Newborn, Pregnancy Outcome, Infant, Hyperammonemia, medicine.disease, Ornithine Carbamoyltransferase Deficiency Disease, Maternal Mortality, 030104 developmental biology, Systematic review, Female, medicine.symptom, business
Abstract: Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked urea cycle disorder. Maternal OTCD can lead to life-threatening hyperammonemia if untreated. We aimed to compare the outcomes of maternal OTCD when diagnosis is known prior to pregnancy to when diagnosis is made during pregnancy. We performed a systematic literature review on maternal OTCD using the databases Ovid MEDLINE and PubMed from 1982 through 2018. Studies were included if addressed maternal OTCD signs, symptoms, and detailed pregnancy outcomes. We calculated the median or the mean for continuous variables and percentages for categorical variables. Of 36 cases of maternal OTCD, 20 (55%) were diagnosed prior to pregnancy while 16 (45%) were not. In the 20 patients diagnosed prior to pregnancy, 7 (35%) had either a neurologic or psychiatric presentation during pregnancy or postpartum. Two hyperammonemic patients (11%) experienced ICU admission, dialysis, and coma with no maternal deaths. All had a favorable outcome. In the 16 patients not known to have maternal OTCD prior to pregnancy, 13 (81%) had neurologic or psychiatric presentation during pregnancy or postpartum. Four presented with hyperemesis gravidarum. Eleven (69%) hyperammonemic patients had ICU admission and coma and 7 (47%) of them had dialysis. There were 5 (31%) maternal deaths. Three patients (19%) had prolonged hospitalization course. Overall, three male neonatal deaths were reported. Three other male children had liver transplant. Maternal OTCD is associated with high maternal and neonatal morbidity and mortality when diagnosis is made during pregnancy compared to when diagnosis is known prior to pregnancy.
Published: 2019
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37. Management of bone disease in cystinosis: Statement from an international conference

Author: Erik Harms, Susanne Bechtold, Nadine Herzig, Malcolm Lewis, Justine Bacchetta, William A. Gahl, Alexey Tsygin, Ewa Elenberg, Fernando Santos, Oliver Greil, Noelle Cassidy, Karl P. Schlingmann, Neveen A. Soliman, Atif Awan, Gema Ariceta, Frank Rauch, Dieter Haffner, Elena Levtchenko, Aude Servais, Jozef Zustin, Bernd Hoppe, Rezan Topaloglu, Galina Nesterova, Koenraad Veys, Carsten Bergmann, Ulrike Treikauskas, Christian Koeppl, Geroges Deschenes, Katharina Hohenfellner, Clodagh Sweeney, Guenther Steidle, and Rodo O. von Vigier
Subjects: Male, Pediatrics, Cystinosis, Administration, Oral, Research & Experimental Medicine, NEPHROPATHIC CYSTINOSIS, SHORT CHILDREN, CKD‐MBD, Renal osteodystrophy, SCLEROSTIN, cystinosis metabolic bone disease, Genetics (clinical), Genetics & Heredity, Osteomalacia, Disease Management, cystinosis, Medicine, Research & Experimental, Original Article, Female, Bone Diseases, GROWTH-HORMONE, Life Sciences & Biomedicine, CYSTEAMINE THERAPY, medicine.medical_specialty, Cysteamine, hypophosphatemic rickets, Metabolic bone disease, Endocrinology & Metabolism, Nephropathic Cystinosis, CKD-MBD, Genetics, medicine, Humans, TOPICAL CYSTEAMINE, Science & Technology, business.industry, Fanconi syndrome, KIDNEY-DISEASE, Original Articles, Fanconi Syndrome, medicine.disease, CRYSTALS, Hypophosphatemic Rickets, MINERAL DENSITY, business, chronic kidney disease, RENAL FANCONI SYNDROME, transplantation, Kidney disease
Abstract: Cystinosis is an autosomal recessive storage disease due to impaired transport of cystine out of lysosomes. Since the accumulation of intracellular cystine affects all organs and tissues, the management of cystinosis requires a specialized multidisciplinary team consisting of pediatricians, nephrologists, nutritionists, ophthalmologists, endocrinologists, neurologists' geneticists, and orthopedic surgeons. Treatment with cysteamine can delay or prevent most clinical manifestations of cystinosis, except the renal Fanconi syndrome. Virtually all individuals with classical, nephropathic cystinosis suffer from cystinosis metabolic bone disease (CMBD), related to the renal Fanconi syndrome in infancy and progressive chronic kidney disease (CKD) later in life. Manifestations of CMBD include hypophosphatemic rickets in infancy, and renal osteodystrophy associated with CKD resulting in bone deformities, osteomalacia, osteoporosis, fractures, and short stature. Assessment of CMBD involves monitoring growth, leg deformities, blood levels of phosphate, electrolytes, bicarbonate, calcium, and alkaline phosphatase, periodically obtaining bone radiographs, determining levels of critical hormones and vitamins, such as thyroid hormone, parathyroid hormone, 25(OH) vitamin D, and testosterone in males, and surveillance for nonrenal complications of cystinosis such as myopathy. Treatment includes replacement of urinary losses, cystine depletion with oral cysteamine, vitamin D, hormone replacement, physical therapy, and corrective orthopedic surgery. The recommendations in this article came from an expert meeting on CMBD that took place in Salzburg, Austria, in December 2016. ispartof: JOURNAL OF INHERITED METABOLIC DISEASE vol:42 issue:5 pages:1019-1029 ispartof: location:United States status: published
Published: 2019
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38. Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification

Author: Elena-Raluca Nicoli, Mary R. Weston, Mary Hackbarth, Alissa Becerril, Austin Larson, Wadih M. Zein, Peter R. Baker, John Douglas Burke, Heidi Dorward, Mariska Davids, Yan Huang, David R. Adams, Patricia M. Zerfas, Dong Chen, Thomas C. Markello, Camilo Toro, Tim Wood, Gene Elliott, Mylinh Vu, Wei Zheng, Lisa J. Garrett, Cynthia J. Tifft, William A. Gahl, Debra L. Day-Salvatore, Joseph A. Mindell, May Christine V. Malicdan, Maria T. Acosta, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Alan H. Beggs, Gill Bejerano, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Shirley Sutton, David A. Sweetser, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: Male, 0301 basic medicine, Albinism, Antiporter, Vacuole, Article, Organomegaly, Mice, Xenopus laevis, 03 medical and health sciences, 0302 clinical medicine, Chloride Channels, Lysosome, Genetics, medicine, Lysosomal storage disease, Animals, Humans, Genetics (clinical), Hypopigmentation, biology, Chemistry, Genetic Variation, Infant, Fibroblasts, Hydrogen-Ion Concentration, medicine.disease, Molecular biology, Lysosomal Storage Diseases, 030104 developmental biology, medicine.anatomical_structure, Oocytes, biology.protein, Female, CLCN7, medicine.symptom, Lysosomes, Acids, 030217 neurology & neurosurgery, Intracellular
Abstract: Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl(−)/H(+) exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.
Published: 2019
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39. Glycomics in rare diseases: from diagnosis tomechanism

Author: Mohd A. Raihan, Mariska Davids, May Christine V. Malicdan, William A. Gahl, Miao He, David H. Adams, Lynne A. Wolfe, Megan S. Kane, Camilo Toro, Xueli Li, Cynthia J. Tifft, and Cornelius F. Boerkoel
Subjects: 0301 basic medicine, Protein glycosylation, Glycan, Glycosylation, Disease, Bioinformatics, Glycomics, 03 medical and health sciences, chemistry.chemical_compound, Rare Diseases, 0302 clinical medicine, Physiology (medical), Humans, Medicine, Exome sequencing, biology, business.industry, Biochemistry (medical), Public Health, Environmental and Occupational Health, General Medicine, Glycome, Phenotype, carbohydrates (lipids), 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, biology.protein, business
Abstract: The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) studies rare genetic disorders not only to achieve diagnoses, but to understand human biology. To ascertain the contribution of protein glycosylation to rare diseases, the NIH UDP used mass spectrometry to agnostically identify abnormalities of N-linked and O-linked glycans in plasma and free oligosaccharides in the urine of 207 patients. 60% of UDP patients had a glycome profile that deviated from control values in at least 1 fluid. Additional evaluation of the fibroblast glycome in 66 patients with abnormalities in plasma and/or urine revealed a consistent glycome phenotype in 83% of these cases. Many of these patients may have secondary glycosylation defects, since it is unlikely that they all have congenital disorders of glycosylation (CDGs). In fact, whole exome sequencing revealed only a few patients with CDGs, along with several others having disorders indirectly altering glycosylation. In summary, we describe a biochemical phenotyping screen to identify defects in protein glycosylation that can elucidate mechanisms of disease among NIH UDP patients.
Published: 2019
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40. Hermansky-Pudlak syndrome and oculocutaneous albinism in Chinese children with pigmentation defects and easy bruising

Author: Carlos Ferreira, Bradley Power, Dong Chen, Joshi Stephen, Kevin J. O'Brien, May Christine V. Malicdan, Wadih M. Zein, David R. Adams, Marjan Huizing, Wendy J. Introne, William A. Gahl, and Bernadette R. Gochuico
Subjects: Blood Platelets, Male, 0301 basic medicine, medicine.medical_specialty, Genotype, lcsh:Medicine, 030105 genetics & heredity, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Genotype-phenotype distinction, Microscopy, Electron, Transmission, hemic and lymphatic diseases, Humans, Medicine, Missense mutation, Pharmacology (medical), Child, Exome, Genetics (clinical), Hypopigmentation, Chinese, integumentary system, business.industry, Research, Platelet, lcsh:R, Hermansky-Pudlak syndrome, General Medicine, Oculocutaneous albinism, medicine.disease, Dermatology, eye diseases, Pedigree, Dense granule, Albinism, Oculocutaneous, Hermanski-Pudlak Syndrome, Child, Preschool, Bruising, Mutation, Etiology, Female, medicine.symptom, Hermansky–Pudlak syndrome, business, 030217 neurology & neurosurgery
Abstract: Background Determining the etiology of oculocutaneous albinism is important for proper clinical management and to determine prognosis. The purpose of this study was to genotype and phenotype eight adopted Chinese children who presented with oculocutaneous albinism and easy bruisability. Results The patients were evaluated at a single center; their ages ranged from 3 to 8 years. Whole exome or direct sequencing showed that two of the children had Hermansky-Pudlak syndrome (HPS) type-1 (HPS-1), one had HPS-3, one had HPS-4, and four had non-syndromic oculocutaneous albinism associated with TYR variants (OCA1). Two frameshift variants in HPS1 (c.9delC and c.1477delA), one nonsense in HPS4 (c.416G > A), and one missense variant in TYR (c.1235C > T) were unreported. The child with HPS-4 is the first case with this subtype reported in the Chinese population. Hypopigmentation in patients with HPS was mild compared to that in OCA1 cases, who had severe pigment defects. Bruises, which may be more visible in patients with hypopigmentation, were found in all cases with either HPS or OCA1. Whole mount transmission electron microscopy demonstrated absent platelet dense granules in the HPS cases; up to 1.9 mean dense granules per platelet were found in those with OCA1. Platelet aggregation studies in OCA1 cases were inconclusive. Conclusions Clinical manifestations of oculocutaneous albinism and easy bruisability may be observed in children with HPS or OCA1. Establishing definitive diagnoses in children presenting with these phenotypic features is facilitated by genetic testing. Non-syndromic oculocutaneous albinism and various HPS subtypes, including HPS-4, are found in children of Chinese ancestry.
Published: 2019
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41. Novel mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis without visual impairment in two unrelated patients

Author: Prashant Sharma, William A. Gahl, Babak Behnam, Cynthia J. Tifft, Camille Wang, May Christine V. Malicdan, Mariska Davids, Camilo Toro, Wadih M. Zein, William Brian Gallantine, David R. Adams, Xenia Chepa-Lotrea, and Joseph J. Chin
Subjects: Adult, Male, 0301 basic medicine, Proband, Pathology, medicine.medical_specialty, Batten disease, Adolescent, Endocrinology, Diabetes and Metabolism, Vision Disorders, 030105 genetics & heredity, Biochemistry, Lipofuscin, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Neuronal Ceroid-Lipofuscinoses, Genetics, medicine, Humans, Exome, Child, Molecular Biology, Exome sequencing, business.industry, Endoplasmic reticulum, High-Throughput Nucleotide Sequencing, Membrane Proteins, Fibroblasts, medicine.disease, Phenotype, United States, Transmembrane protein, Pedigree, National Institutes of Health (U.S.), Mutation, Female, Neuronal ceroid lipofuscinosis, business, 030217 neurology & neurosurgery
Abstract: CLN6 is a transmembrane protein located in the endoplasmic reticulum that is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis (LINCL), and teenage and adult onset NCL without visual impairment. Here we describe two pediatric patients with LINCL from unrelated families who were evaluated at the National Institutes of Health. Both children exhibited typical phenotypes associated with LINCL except that they lacked the expected visual impairment. Whole exome sequencing identified novel biallelic mutations in CLN6, i.e., c.218-220dupGGT (p.Trp73dup) and c.296A > G (p.Lys99Arg) in Proband 1 and homozygous c.723G > T (p.Met241Ile) in Proband 2. Expression analysis in dermal fibroblasts showed a small increase in CLN6 protein levels. Electron micrographs of these fibroblasts demonstrated large numbers of small membrane-bound vesicles, in addition to lipofuscin deposits. LysoTracker™ Red intensity was increased in fibroblasts from both patients. This study supports a role for CLN6 in lysosomal homeostasis, and highlights the importance of considering CLN6 mutations in the diagnosis of Batten Disease even in patients with normal vision.
Published: 2019
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42. Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails

Author: Grazia M.S. Mancini, Wim Vermeulen, Rebecca Meyer-Schuman, Marjon van Slegtenhorst, Marisa I. Mendes, Catherine Groden, Shino Shimada, Thomas Christian, Anja Raams, Desirée E.C. Smith, Ya-Ming Hou, L.M. Hussaarts-Odijk, Gajja S. Salomons, May Christine V. Malicdan, Martina Wilke, Molly E. Kuo, Eric van der Meijden, Anthony Antonellis, Arjan F. Theil, William A. Gahl, Frans W. Verheijen, Anneke Kievit, Wendy J. Introne, AGEM - Inborn errors of metabolism, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Clinical chemistry, Amsterdam Reproduction & Development (AR&D), Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Molecular Genetics, and Clinical Genetics
Subjects: Adult, Male, Microcephaly, Developmental Disabilities, Sequence Homology, Genes, Recessive, Locus (genetics), Biology, Compound heterozygosity, Amino Acyl-tRNA Synthetases, Nail Diseases, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, Charcot-Marie-Tooth Disease, Locus heterogeneity, Report, Genetics, medicine, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Allele, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Aminoacyl tRNA synthetase, 030305 genetics & heredity, Prognosis, medicine.disease, Phenotype, Pedigree, Complementation, chemistry, Mutation, Female, Hair Diseases
Abstract: Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging tRNA molecules with cognate amino acids. Consistent with the essential function and ubiquitous expression of ARSs, mutations in 32 of the 37 ARS-encoding loci cause severe, early-onset recessive phenotypes. Previous genetic and functional data suggest a loss-of-function mechanism; however, our understanding of the allelic and locus heterogeneity of ARS-related disease is incomplete. Cysteinyl-tRNA synthetase (CARS) encodes the enzyme that charges tRNA Cys with cysteine in the cytoplasm. To date, CARS variants have not been implicated in any human disease phenotype. Here, we report on four subjects from three families with complex syndromes that include microcephaly, developmental delay, and brittle hair and nails. Each affected person carries bi-allelic CARS variants: one individual is compound heterozygous for c.1138C>T (p.Gln380 ∗ ) and c.1022G>A (p.Arg341His), two related individuals are compound heterozygous for c.1076C>T (p.Ser359Leu) and c.1199T>A (p.Leu400Gln), and one individual is homozygous for c.2061dup (p.Ser688Glnfs ∗ 2). Measurement of protein abundance, yeast complementation assays, and assessments of tRNA charging indicate that each CARS variant causes a loss-of-function effect. Compared to subjects with previously reported ARS-related diseases, individuals with bi-allelic CARS variants are unique in presenting with a brittle-hair-and-nail phenotype, which most likely reflects the high cysteine content in human keratins. In sum, our efforts implicate CARS variants in human inherited disease, expand the locus and clinical heterogeneity of ARS-related clinical phenotypes, and further support impaired tRNA charging as the primary mechanism of recessive ARS-related disease.
Published: 2019
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43. Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

Author: Keren Machol, Justine Rousseau, Sophie Ehresmann, Thomas Garcia, Thi Tuyet Mai Nguyen, Rebecca C. Spillmann, Jennifer A. Sullivan, Vandana Shashi, Yong-hui Jiang, Nicholas Stong, Elise Fiala, Marcia Willing, Rolph Pfundt, Tjitske Kleefstra, Megan T. Cho, Heather McLaughlin, Monica Rosello Piera, Carmen Orellana, Francisco Martínez, Alfonso Caro-Llopis, Sandra Monfort, Tony Roscioli, Cheng Yee Nixon, Michael F. Buckley, Anne Turner, Wendy D. Jones, Peter M. van Hasselt, Floris C. Hofstede, Koen L.I. van Gassen, Alice S. Brooks, Marjon A. van Slegtenhorst, Katherine Lachlan, Jessica Sebastian, Suneeta Madan-Khetarpal, Desai Sonal, Naidu Sakkubai, Julien Thevenon, Laurence Faivre, Alice Maurel, Slavé Petrovski, Ian D. Krantz, Jennifer M. Tarpinian, Jill A. Rosenfeld, Brendan H. Lee, Philippe M. Campeau, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F. Batzli, Alan H. Beggs, Babak Behnam, Anna Bican, David P. Bick, Camille L. Birch, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Shan Chen, Gary D. Clark, Terra R. Coakley, Joy D. Cogan, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Ani Dillon, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Carlos Ferreira, Brent L. Fogel, Noah D. Friedman, William A. Gahl, Emily Glanton, Rena A. Godfrey, David B. Goldstein, Sarah E. Gould, Jean-Philippe F. Gourdine, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Matthew R. Herzog, Ingrid A. Holm, Jason Hom, Ellen M. Howerton, Yong Huang, Howard J. Jacob, Mahim Jain, Jean M. Johnston, Angela L. Jones, Isaac S. Kohane, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Seema R. Lalani, C. Christopher Lau, Jozef Lazar, Hane Lee, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Allen Lipson, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Matthew Might, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Loren D.M. Pena, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Chloe M. Reuter, Amy K. Robertson, Lance H. Rodan, Jacinda B. Sampson, Susan L. Samson, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Kimberly Splinter, Joan M. Stoler, David A. Sweetser, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Zaheer M. Valivullah, Eric Vilain, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Patricia A. Ward, Katrina M. Waters, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, Diane B. Zastrow, Allison Zheng, and Clinical Genetics
Subjects: Male, 0301 basic medicine, Hypertrichosis, speech delay, Bafopathy, Developmental Disabilities, CACNB4, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Bafopathy, developmental delay, dysmorphisms, genotype-phenotype correlation, intellectual disability, neurodevelopmental disorder, speech delay, transcriptome, Genetics(clinical), Child, Genetics (clinical), Genetics, Syndrome, Hypotonia, DNA-Binding Proteins, developmental delay, Corticogenesis, intellectual disability, Child, Preschool, Speech delay, Female, medicine.symptom, Hand Deformities, Congenital, dysmorphisms, Adolescent, Micrognathism, genotype-phenotype correlation, Biology, Chromatin remodeling, 03 medical and health sciences, Journal Article, medicine, Humans, Abnormalities, Multiple, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], medicine.disease, neurodevelopmental disorder, Reelin Protein, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Face, Mutation, biology.protein, transcriptome, Neck, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Contains fulltext : 202800.pdf (Publisher’s version ) (Open Access) SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.
Published: 2019
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44. An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Author: Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, Frédéric M. Vaz, Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Methodology, Epidemiology and Data Science, APH - Personalized Medicine, Laboratory for General Clinical Chemistry, ARD - Amsterdam Reproduction and Development, Human genetics, ACS - Atherosclerosis & ischemic syndromes, and Amsterdam Reproduction & Development (AR&D)
Subjects: Candidate gene, Hereditary spastic paraplegia, Undiagnosed Diseases Network, Neurological disorder, Biology, medicine.disease, Molecular biology, Article, Biochemical phenotype, Bilateral Cataracts, Gene panel, medicine, Ether lipid synthesis, In patient, Genetics (clinical)
Abstract: Author(s): Ferdinandusse, Sacha; McWalter, Kirsty; Te Brinke, Heleen; IJlst, Lodewijk; Mooijer, Petra M; Ruiter, Jos PN; van Lint, Alida EM; Pras-Raves, Mia; Wever, Eric; Millan, Francisca; Guillen Sacoto, Maria J; Begtrup, Amber; Tarnopolsky, Mark; Brady, Lauren; Ladda, Roger L; Sell, Susan L; Nowak, Catherine B; Douglas, Jessica; Tian, Cuixia; Ulm, Elizabeth; Perlman, Seth; Drack, Arlene V; Chong, Karen; Martin, Nicole; Brault, Jennifer; Brokamp, Elly; Toro, Camilo; Gahl, William A; Macnamara, Ellen F; Wolfe, Lynne; Undiagnosed Diseases Network; Waisfisz, Quinten; Zwijnenburg, Petra JG; Ziegler, Alban; Barth, Magalie; Smith, Rosemarie; Ellingwood, Sara; Gaebler-Spira, Deborah; Bakhtiari, Somayeh; Kruer, Michael C; van Kampen, Antoine HC; Wanders, Ronald JA; Waterham, Hans R; Cassiman, David; Vaz, Frederic M | Abstract: PurposeIn this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).MethodsFollowing next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.ResultsAll patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.ConclusionHeterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
Published: 2021
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45. PARK7-Related Early Onset Parkinson Disease in the Setting of Complete Uniparental Isodisomy of Chromosome 1

Author: Camilo Toro, Rachel Bishop, William A. Gahl, Changrui Xiao, Thomas C. Markello, Catherine Groden, and Wadih M. Zein
Subjects: Genetics, business.industry, Mutant allele, PARK7, Chromosome, Disease, Asymptomatic, Uniparental Isodisomy, medicine, Neurology (clinical), medicine.symptom, business, Gene, Clinical/Scientific Notes, Genetics (clinical), Early onset
Abstract: Approximately 10% of Parkinson disease (PD) has a monogenic basis. PARK7 is a rare recessive form of early-onset PD caused by mutations in the gene PARK7 (formerly DJ1 ).1 As expected for a recessive disorder, PARK7 patients usually inherit 1 mutant allele from each parent; in fact, most reported cases have occurred in consanguineous families. We report an adult with early onset PD who inherited 2 identical pathogenic PARK7 variants from her asymptomatic father, a carrier for the same variant, via complete uniparental isodisomy (UPD) of chromosome 1. The authors wish to thank patients, families, consultants, and referring physicians participating in the NIH Undiagnosed Diseases Program.
Published: 2021

46. Inflammatory bowel disease in Hermansky-Pudlak syndrome: a retrospective single-centre cohort study

Author: Bernadette R. Gochuico, Theo Heller, Wendy J. Introne, Kevin J. O'Brien, X Parisi, William A. Gahl, N R Shelman, May Christine V. Malicdan, and Melissa A. Merideth
Subjects: Adult, Male, medicine.medical_specialty, Abdominal pain, Cryptitis, Adolescent, Genotype, medicine.medical_treatment, digestive system, Inflammatory bowel disease, Gastroenterology, Young Adult, Internal medicine, Internal Medicine, medicine, Humans, Age of Onset, Child, Defecation, Colectomy, Retrospective Studies, business.industry, Infant, Bowel resection, Middle Aged, medicine.disease, Inflammatory Bowel Diseases, eye diseases, digestive system diseases, Hematochezia, Infliximab, Abdominal Pain, Hermanski-Pudlak Syndrome, Child, Preschool, Female, medicine.symptom, Age of onset, business, Gastrointestinal Hemorrhage, medicine.drug
Abstract: Background Knowledge about inflammatory bowel disease (IBD) in patients with Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles, could provide insights into IBD in general. Objective To expand the understanding of IBD in patients with HPS. Methods Retrospective review of records from patients with HPS evaluated at the National Institutes of Health Clinical Center from 1995 to 2019 was conducted. Clinical features of IBD, genotyping results and histologic findings of colectomy specimens were analysed. Results IBD affected 37 (14.2%; 12 male, 25 female) of 261 patients with HPS. Median age of onset was 17 years; range was 1 to 52 years. The most common symptoms of HPS IBD were hematochezia, abdominal pain and loose stools. Fistulae or extra-intestinal manifestations developed in 30% or 22%, respectively. Genotyping showed that patients with biallelic variants in HPS1, HPS3, HPS4 or HPS6 were diagnosed with IBD. Six children had very early-onset IBD. Patients with HPS-3 had mild manifestations of IBD. Medical therapy and bowel resection were utilized to treat 73% and 35% of patients with HPS IBD, respectively; 7 of 13 patients receiving anti-tumor necrosis factor alpha therapy had prolonged clinical responses. Active cryptitis, chronic inflammatory changes, granulomas and ceroid lipofuscinosis were histopathologic findings in three colectomy specimens. Conclusions IBD resembling Crohn's disease affects some patients with HPS; genetic heterogeneity is a feature of HPS IBD. HPS3 is a new gene associated with human IBD. Very early-onset IBD can develop in HPS.
Published: 2021

47. Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

Author: Lance H. Rodan, Rebecca C. Spillmann, Harley T. Kurata, Shawn M. Lamothe, Jasmine Maghera, Rami Abou Jamra, Anna Alkelai, Stylianos E. Antonarakis, Isis Atallah, Omer Bar-Yosef, Frédéric Bilan, Kathrine Bjorgo, Xavier Blanc, Patrick Van Bogaert, Yoav Bolkier, Lindsay C. Burrage, Björn U. Christ, Jorge L. Granadillo, Patricia Dickson, Kirsten A. Donald, Christèle Dubourg, Aviva Eliyahu, Lisa Emrick, Kendra Engleman, Michaela Veronika Gonfiantini, Jean-Marc Good, Judith Kalser, Chiara Kloeckner, Guus Lachmeijer, Marina Macchiaiolo, Francesco Nicita, Sylvie Odent, Emily O’Heir, Xilma Ortiz-Gonzalez, Marta Pacio-Miguez, María Palomares-Bralo, Loren Pena, Konrad Platzer, Mathieu Quinodoz, Emmanuelle Ranza, Jill A. Rosenfeld, Eliane Roulet-Perez, Avni Santani, Fernando Santos-Simarro, Ben Pode-Shakked, Cara Skraban, Rachel Slaugh, Andrea Superti-Furga, Isabelle Thiffault, Richard H. van Jaabrsveld, Marie Vincent, Hong-Gang Wang, Pia Zacher, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, null Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. PhillipsIII, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Eric Rush, Geoffrey S. Pitt, Ping Yee Billie Au, Boston Children's Hospital, University of Alberta, Universität Leipzig [Leipzig], Geneva University Hospital (HUG), Tel Aviv University [Tel Aviv], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Baylor College of Medicine (BCM), Baylor University, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Lausanne University Hospital, Centre de référence Maladies Rares CLAD-Ouest [Rennes], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Children’s Hospital of Philadelphia (CHOP ), Hospital Universitario La Paz, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Duke University [Durham], University of Kansas Medical Center [Lawrence], University of Missouri System, Children's Mercy Hospital [Kansas City], Weill Cornell Medicine [New York], University of Calgary, Research reported in this paper was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under award number(s) (U01HG007709 [Baylor College of Medicine] and U01HG007672 [Duke University to V.S.]). Additional funding for this project was under award number 1RO1HD090132-01A1 (Cornell University to G.P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional funding was provided by a Canadian Institutes of Health Research Grant (MOP-97988 to H.T.K.), and a Rowland and Muriel Haryett Fellowship (University of Alberta, to S.M.L.) and a fellowship from the Ministry of Education and Research of the Community of Madrid to M.P.M. (B2017/BMD-3721), and microgrant from the Rare Disease Foundation (P.Y.B.A. and H.T.K.). Sequencing and analysis was supported by the National Human Genome Research Institute grants UM1 HG008900 and R01 HG009141. K.A.D., B.C., and E.O. were supported the National Institute of Mental Health U01 MH119689., Universität Leipzig, Columbia University Medical Center (CUMC), Columbia University [New York], Tel Aviv University (TAU), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Unité de recherche de l'institut du thorax (ITX-lab), University of Kansas Medical Center [Kansas City, KS, USA], Weill Cornell Medicine [Cornell University], and Cornell University [New York]
Subjects: Ataxia, Calcium Channels, L-Type, Long QT syndrome, Timothy syndrome, Bioinformatics, Article, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual disability, medicine, Missense mutation, Humans, Autistic Disorder, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, Hypotonia, Long QT Syndrome, Phenotype, Autism, Syndactyly, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; Purpose:CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.Methods:We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.Results:Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.Conclusion:We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.
Published: 2020
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48. Forkhead box R1-mediated stress response linked to a case of human microcephaly and brain atrophy

Author: Rui Hong, Malicdan Cm, Niu S, Uwe Beffert, Bertherat Fl, Lynne A. Wolfe, Mota A, William A. Gahl, T. C. Markello, Angela Ho, David R. Adams, and Christine S. Cheng
Subjects: Microcephaly, Chaperone (protein), medicine, biology.protein, Repressor, Postnatal microcephaly, Biology, Heat shock, medicine.disease, Phenotype, Transcription factor, HSPA1A, Cell biology
Abstract: Forkhead box (Fox) family transcription factors are highly conserved and play essential roles in a wide range of cellular and developmental processes. We report an individual with severe neurological symptoms including postnatal microcephaly, progressive brain atrophy and global developmental delay associated with ade novomissense variant (M280L) in theFOXR1gene. At the protein level, M280L impaired FOXR1 expression and induced a nuclear aggregate phenotype due to protein misfolding and proteolysis. RNAseq and pathway analysis showed that FOXR1 acts as both a transcriptional activator and repressor with central roles in heat shock response, chaperone cofactor-dependent protein refolding and cellular response to stress. Indeed, FOXR1 expression is increased in response to cellular stress, a process in which it directly controlsHSPA6, HSPA1AandDHRS2transcripts. Meanwhile, the ability of the M280L mutant to respond to stress is compromised, in part due to impaired regulation of downstream target genes that are involved in the stress response pathway. Combined, these results suggest FOXR1 plays a role in cellular stress and is necessary for normal brain development.
Published: 2020
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49. Prevalence of Hypothyroidism in Patients With Erdheim-Chester Disease

Author: Juvianee Estrada-Veras, Georgios Z. Papadakis, Kevin O'Brien, Fady Hannah-Shmouni, Joanna Klubo-Gwiezdzinska, Rahul Dave, Monica C. Skarulis, Ninet Sinaii, Amit Tirosh, Skand Shekhar, William A. Gahl, Jorge A Irizarry-Caro, Brent S. Abel, and Bernadette R. Gochuico
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Erdheim-Chester Disease, endocrine system diseases, genetic structures, Levothyroxine, Thyroid Function Tests, Thyroid function tests, Cohort Studies, Hypothyroidism, medicine, Central hypothyroidism, Prevalence, Humans, Original Investigation, medicine.diagnostic_test, business.industry, Research, Thyroid, Primary hypothyroidism, General Medicine, Odds ratio, medicine.disease, Causality, Histiocytosis, Online Only, Diabetes and Endocrinology, medicine.anatomical_structure, Cross-Sectional Studies, Disease Progression, Female, business, medicine.drug, Cohort study
Abstract: Key Points Question What is the prevalence of hypothalamic-pituitary-thyroid dysfunction in patients with Erdheim-Chester disease (ECD)? Findings In this cross-sectional study of 61 patients with ECD, the prevalence of central and primary hypothyroidism was 9.8% and 18.0%, respectively, in patients with ECD, higher than the corresponding rates of 0.1% and 4.7%, respectively, in the community. Meaning The findings of this study suggest that clinicians should consider screening for hypothyroidism in patients with ECD., This cross-sectional study assesses rates of hypothalamus-pituitary-thyroid dysfunction in patients with Erdheim-Chester disease., Importance Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis affecting multiple organs and commonly caused by somatic pathogenic variants in BRAF V600E and mitogen-activated protein kinase genes. Clinical features of ECD result from histiocytic involvement of various tissues; while endocrine involvement in ECD occurs frequently, the prevalence of central or primary hypothyroidism has not been thoroughly investigated. Objective To assess hypothalamus-pituitary-thyroid (HPT) dysfunction in patients with ECD. Design, Setting, and Participants This cross-sectional study included 61 patients with ECD who were enrolled in a natural history study at a tertiary care center between January 2011 and December 2018. ECD was diagnosed on the basis of clinical, genetic, and histopathological features. Data were analyzed in March 2020. Exposure Diagnosis of ECD. Main Outcomes and Measures Main outcome was the prevalence of thyroid dysfunction in adults with ECD compared with community estimates. Patients underwent baseline evaluation with a thyroid function test, including thyrotropin, free thyroxine (fT4), and total thyroxine (T4), and sellar imaging with magnetic resonance imaging or computed tomography scan. The association of HPT dysfunction was assessed for differences in age, sex, body mass index, BRAF V600E status, high sensitivity C-reactive protein level, sellar imaging, and pituitary hormonal dysfunction. Results A total of 61 patients with ECD (46 [75%] men; mean [SD] age, 54.3 [10.9] years) were evaluated. Seventeen patients (28%) had hypothyroidism requiring levothyroxine therapy. The prevalence of both central and primary hypothyroidism were higher than community estimates (central hypothyroidism: 9.8% vs 0.1%; odds ratio, 109.0; 95% CI, 37.4-260.6; P
Published: 2020

50. Strategic vision for improving human health at The Forefront of Genomics

Author: Paul P. Liu, Allison Mandich, Chris Gunter, Elise A. Feingold, Adam Felsenfeld, Teri A. Manolio, Valentina Di Francesco, Kris A. Wetterstrand, Daniel L. Kastner, Leslie G. Biesecker, Jyoti G. Dayal, Britny J. Kish, Vence L. Bonham, Anastasia L. Wise, Elaine A. Ostrander, William A. Gahl, Benjamin D. Solomon, Susan Vasquez, William J. Pavan, Laura Lyman Rodriguez, David J. Kaufman, Carla Easter, Lawrence C. Brody, Adam M. Phillippy, Sarah A. Bates, Eric D. Green, Christopher Wellington, Carolyn M. Hutter, Bettie J. Graham, and Darryl Leja
Subjects: 0301 basic medicine, medicine.medical_specialty, Biomedical Research, Process (engineering), Genomics, Translational research, Article, Translational Research, Biomedical, 03 medical and health sciences, 0302 clinical medicine, Political science, medicine, Mainstream, Humans, Social Change, Everyday life, Strategic planning, Multidisciplinary, Genome, Human, Public health, COVID-19, Human genetics, United States, National Human Genome Research Institute (U.S.), 030104 developmental biology, Engineering ethics, Public Health, 030217 neurology & neurosurgery
Abstract: Starting with the launch of the Human Genome Project three decades ago, genomics has become progressively entrenched within the bedrock of the biomedical research enterprise. Capitalizing on the momentum of the project’s successful completion in 2003, genomics now regularly plays a central and catalytic role in basic and translational research, and studies increasingly demonstrate the vital role that genomic information can play in clinical care. Looking ahead, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into virtually all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics in everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to capture input about the future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we articulate the highest-priority elements envisioned for the cutting-edge of human genomics going forward – that is, at “The Forefront of Genomics.”
Published: 2020
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