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

Author

Morimoto, Marie, Bhambhani, Vikas, Gazzaz, Nour, Davids, Mariska, Sathiyaseelan, Paalini, Macnamara, Ellen F, Lange, Jennifer, Lehman, Anna, Zerfas, Patricia M, Murphy, Jennifer L, Acosta, Maria T, Wang, Camille, Alderman, Emily, Reichert, Sara, Thurm, Audrey, Adams, David R, Introne, Wendy J, Gorski, Sharon M, Boerkoel, Cornelius F, Gahl, William A, Tifft, Cynthia J, and Malicdan, May Christine V

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Clinical Research, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Undiagnosed Diseases Network, Medical biotechnology
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

2. Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann–Pick disease types A, B and A/B)

Author

Geberhiwot, Tarekegn, Wasserstein, Melissa, Wanninayake, Subadra, Bolton, Shaun Christopher, Dardis, Andrea, Lehman, Anna, Lidove, Olivier, Dawson, Charlotte, Giugliani, Roberto, Imrie, Jackie, Hopkin, Justin, Green, James, de Vicente Corbeira, Daniel, Madathil, Shyam, Mengel, Eugen, Ezgü, Fatih, Pettazzoni, Magali, Sjouke, Barbara, Hollak, Carla, Vanier, Marie T., McGovern, Margaret, and Schuchman, Edward

Published
2023
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4. Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study

Author

Boycott, Kym, Brudno, Michael, Bernier, Francois, van Karnebeek, Clara, Dyment, David, Kernohan, Kristin, Innes, Micheil, Lamont, Ryan, Parboosingh, Jillian, Marshall, Deborah, Marshall, Christian, Mendoza, Roberto, Dowling, James, Hayeems, Robin, Knoppers, Bartha, Lehman, Anna, Mostafavi, Sara, Hartley, Taila, Acker, Meryl, Fooks, Katharine, Gillespie, Meredith K., Price, E. Magda, Graham, Ian D., White-Brown, Alexandre, MacKay, Layla, Macdonald, Stella K., Brady, Lauren, Hui, Angela Y., Andrews, Joseph D., Chowdhury, Ashfia, Wall, Erika, Soubry, Élisabeth, Ediae, Grace U., Rojas, Samantha, Assamad, Daniel, Tarnopolsky, Mark, Sawyer, Sarah L., Chisholm, Caitlin, Lemire, Gabrielle, Amburgey, Kimberly, Lazier, Joanna, Mendoza-Londono, Roberto, Dowling, James J., Balci, Tugce B., Armour, Christine M., Bhola, Priya T., Costain, Gregory, Dupuis, Lucie, Carter, Melissa, Badalato, Lauren, Richer, Julie, Boswell-Patterson, Christie, Kannu, Peter, Cordeiro, Dawn, Warman-Chardon, Jodi, Graham, Gail, Siu, Victoria Mok, Cytrynbaum, Cheryl, Rusnak, Alison, Aul, Ritu B., Yoon, Grace, Gonorazky, Hernan, McNiven, Vanda, Mercimek-Andrews, Saadet, Guerin, Andrea, Deshwar, Ashish R., Marwaha, Ashish, Weksberg, Rosanna, Karp, Natalya, Campbell, Maggie, Al-Qattan, Sarah, Shuen, Andrew Y., Inbar-Feigenberg, Michal, Cohn, Ronald, Szuto, Anna, Inglese, Cara, Poirier, Myriam, Chad, Lauren, Potter, Beth, and Boycott, Kym M.

Published
2024
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5. Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders

Author

Duncan, Anna R, Polovitskaya, Maya M, Gaitán-Peñas, Héctor, Bertelli, Sara, VanNoy, Grace E, Grant, Patricia E, O’Donnell-Luria, Anne, Valivullah, Zaheer, Lovgren, Alysia Kern, England, Elaina M, Agolini, Emanuele, Madden, Jill A, Schmitz-Abe, Klaus, Kritzer, Amy, Hawley, Pamela, Novelli, Antonio, Alfieri, Paolo, Colafati, Giovanna Stefania, Wieczorek, Dagmar, Platzer, Konrad, Luppe, Johannes, Koch-Hogrebe, Margarete, Jamra, Rami Abou, Neira-Fresneda, Juanita, Lehman, Anna, Boerkoel, Cornelius F, Seath, Kimberly, Clarke, Lorne, Study, CAUSES, van Ierland, Yvette, Argilli, Emanuela, Sherr, Elliott H, Maiorana, Andrea, Diel, Thilo, Hempel, Maja, Bierhals, Tatjana, Estévez, Raúl, Jentsch, Thomas J, Pusch, Michael, and Agrawal, Pankaj B

Subjects
Biological Sciences, Medical Physiology, Biomedical and Clinical Sciences, Genetics, Pediatric, Mental Health, Intellectual and Developmental Disabilities (IDD), Neurosciences, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adolescent, Animals, Child, Child, Preschool, Chloride Channels, Disease Models, Animal, Female, Homozygote, Humans, Infant, Infant, Newborn, Ion Channels, Male, Mice, Mice, Knockout, Mutation, Neurodevelopmental Disorders, Phenotype, CAUSES Study, CLCN, acidification, gain of function, hippocampus, intellectual disability, neurodevelopmental delay, pH sensitivity, voltage gated chloride channel, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3-/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.

Published
2021

7. Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Author

Gillentine, Madelyn A, Wang, Tianyun, Hoekzema, Kendra, Rosenfeld, Jill, Liu, Pengfei, Guo, Hui, Kim, Chang N, De Vries, Bert BA, Vissers, Lisenka ELM, Nordenskjold, Magnus, Kvarnung, Malin, Lindstrand, Anna, Nordgren, Ann, Gecz, Jozef, Iascone, Maria, Cereda, Anna, Scatigno, Agnese, Maitz, Silvia, Zanni, Ginevra, Bertini, Enrico, Zweier, Christiane, Schuhmann, Sarah, Wiesener, Antje, Pepper, Micah, Panjwani, Heena, Torti, Erin, Abid, Farida, Anselm, Irina, Srivastava, Siddharth, Atwal, Paldeep, Bacino, Carlos A, Bhat, Gifty, Cobian, Katherine, Bird, Lynne M, Friedman, Jennifer, Wright, Meredith S, Callewaert, Bert, Petit, Florence, Mathieu, Sophie, Afenjar, Alexandra, Christensen, Celenie K, White, Kerry M, Elpeleg, Orly, Berger, Itai, Espineli, Edward J, Fagerberg, Christina, Brasch-Andersen, Charlotte, Hansen, Lars Kjærsgaard, Feyma, Timothy, Hughes, Susan, Thiffault, Isabelle, Sullivan, Bonnie, Yan, Shuang, Keller, Kory, Keren, Boris, Mignot, Cyril, Kooy, Frank, Meuwissen, Marije, Basinger, Alice, Kukolich, Mary, Philips, Meredith, Ortega, Lucia, Drummond-Borg, Margaret, Lauridsen, Mathilde, Sorensen, Kristina, Lehman, Anna, CAUSES Study, Lopez-Rangel, Elena, Levy, Paul, Lessel, Davor, Lotze, Timothy, Madan-Khetarpal, Suneeta, Sebastian, Jessica, Vento, Jodie, Vats, Divya, Benman, L Manace, Mckee, Shane, Mirzaa, Ghayda M, Muss, Candace, Pappas, John, Peeters, Hilde, Romano, Corrado, Elia, Maurizio, Galesi, Ornella, Simon, Marleen EH, van Gassen, Koen LI, Simpson, Kara, Stratton, Robert, Syed, Sabeen, Thevenon, Julien, Palafoll, Irene Valenzuela, Vitobello, Antonio, Bournez, Marie, Faivre, Laurence, Xia, Kun, SPARK Consortium, Earl, Rachel K, Nowakowski, Tomasz, Bernier, Raphael A, and Eichler, Evan E

Subjects
CAUSES Study, SPARK Consortium, Cortex development, Gene families, Neurodevelopmental disorders, hnRNPs, Genetics, Clinical Sciences
Abstract

BackgroundWith the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.MethodsWe tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.ResultsWe report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.ConclusionsOverall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Published
2021

8. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.

Author

Bryant, Laura, Li, Dong, Cox, Samuel G, Marchione, Dylan, Joiner, Evan F, Wilson, Khadija, Janssen, Kevin, Lee, Pearl, March, Michael E, Nair, Divya, Sherr, Elliott, Fregeau, Brieana, Wierenga, Klaas J, Wadley, Alexandrea, Mancini, Grazia MS, Powell-Hamilton, Nina, van de Kamp, Jiddeke, Grebe, Theresa, Dean, John, Ross, Alison, Crawford, Heather P, Powis, Zoe, Cho, Megan T, Willing, Marcia C, Manwaring, Linda, Schot, Rachel, Nava, Caroline, Afenjar, Alexandra, Lessel, Davor, Wagner, Matias, Klopstock, Thomas, Winkelmann, Juliane, Catarino, Claudia B, Retterer, Kyle, Schuette, Jane L, Innis, Jeffrey W, Pizzino, Amy, Lüttgen, Sabine, Denecke, Jonas, Strom, Tim M, Monaghan, Kristin G, DDD Study, Yuan, Zuo-Fei, Dubbs, Holly, Bend, Renee, Lee, Jennifer A, Lyons, Michael J, Hoefele, Julia, Günthner, Roman, Reutter, Heiko, Keren, Boris, Radtke, Kelly, Sherbini, Omar, Mrokse, Cameron, Helbig, Katherine L, Odent, Sylvie, Cogne, Benjamin, Mercier, Sandra, Bezieau, Stephane, Besnard, Thomas, Kury, Sebastien, Redon, Richard, Reinson, Karit, Wojcik, Monica H, Õunap, Katrin, Ilves, Pilvi, Innes, A Micheil, Kernohan, Kristin D, Care4Rare Canada Consortium, Costain, Gregory, Meyn, M Stephen, Chitayat, David, Zackai, Elaine, Lehman, Anna, Kitson, Hilary, CAUSES Study, Martin, Martin G, Martinez-Agosto, Julian A, Undiagnosed Diseases Network, Nelson, Stan F, Palmer, Christina GS, Papp, Jeanette C, Parker, Neil H, Sinsheimer, Janet S, Vilain, Eric, Wan, Jijun, Yoon, Amanda J, Zheng, Allison, Brimble, Elise, Ferrero, Giovanni Battista, Radio, Francesca Clementina, Carli, Diana, Barresi, Sabina, Brusco, Alfredo, Tartaglia, Marco, Thomas, Jennifer Muncy, Umana, Luis, Weiss, Marjan M, Gotway, Garrett, and Stuurman, KE

Subjects
DDD Study, Care4Rare Canada Consortium, CAUSES Study, Undiagnosed Diseases Network, Cancer, Rare Diseases, Human Genome, Pediatric Research Initiative, Genetics, Biotechnology, 2.1 Biological and endogenous factors
Abstract

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

Published
2020

10. Human complete NFAT1 deficiency causes a triad of joint contractures, osteochondromas, and B-cell malignancy

Author

Sharma, Mehul, Fu, Maggie P., Lu, Henry Y., Sharma, Ashish A., Modi, Bhavi P., Michalski, Christina, Lin, Susan, Dalmann, Joshua, Salman, Areesha, Del Bel, Kate L., Waqas, Meriam, Terry, Jefferson, Setiadi, Audi, Lavoie, Pascal M., Wasserman, Wyeth W., Mwenifumbo, Jill, Kobor, Michael S., Lee, Anna F., Kuchenbauer, Florian, Lehman, Anna, Cheng, Sylvia, Cooper, Anthony, Patel, Millan S., and Turvey, Stuart E.

Published
2022
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11. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Author

Cogné, Benjamin, Ehresmann, Sophie, Beauregard-Lacroix, Eliane, Rousseau, Justine, Besnard, Thomas, Garcia, Thomas, Petrovski, Slavé, Avni, Shiri, McWalter, Kirsty, Blackburn, Patrick R, Sanders, Stephan J, Uguen, Kévin, Harris, Jacqueline, Cohen, Julie S, Blyth, Moira, Lehman, Anna, Berg, Jonathan, Li, Mindy H, Kini, Usha, Joss, Shelagh, von der Lippe, Charlotte, Gordon, Christopher T, Humberson, Jennifer B, Robak, Laurie, Scott, Daryl A, Sutton, Vernon R, Skraban, Cara M, Johnston, Jennifer J, Poduri, Annapurna, Nordenskjöld, Magnus, Shashi, Vandana, Gerkes, Erica H, Bongers, Ernie MHF, Gilissen, Christian, Zarate, Yuri A, Kvarnung, Malin, Lally, Kevin P, Kulch, Peggy A, Daniels, Brina, Hernandez-Garcia, Andres, Stong, Nicholas, McGaughran, Julie, Retterer, Kyle, Tveten, Kristian, Sullivan, Jennifer, Geisheker, Madeleine R, Stray-Pedersen, Asbjorg, Tarpinian, Jennifer M, Klee, Eric W, Sapp, Julie C, Zyskind, Jacob, Holla, Øystein L, Bedoukian, Emma, Filippini, Francesca, Guimier, Anne, Picard, Arnaud, Busk, Øyvind L, Punetha, Jaya, Pfundt, Rolph, Lindstrand, Anna, Nordgren, Ann, Kalb, Fayth, Desai, Megha, Ebanks, Ashley Harmon, Jhangiani, Shalini N, Dewan, Tammie, Coban Akdemir, Zeynep H, Telegrafi, Aida, Zackai, Elaine H, Begtrup, Amber, Song, Xiaofei, Toutain, Annick, Wentzensen, Ingrid M, Odent, Sylvie, Bonneau, Dominique, Latypova, Xénia, Deb, Wallid, CAUSES Study, Redon, Sylvia, Bilan, Frédéric, Legendre, Marine, Troyer, Caitlin, Whitlock, Kerri, Caluseriu, Oana, Murphree, Marine I, Pichurin, Pavel N, Agre, Katherine, Gavrilova, Ralitza, Rinne, Tuula, Park, Meredith, Shain, Catherine, Heinzen, Erin L, Xiao, Rui, Amiel, Jeanne, Lyonnet, Stanislas, Isidor, Bertrand, Biesecker, Leslie G, Lowenstein, Dan, Posey, Jennifer E, and Denommé-Pichon, Anne-Sophie

Subjects
CAUSES Study, Deciphering Developmental Disorders study, Humans, Syndrome, Adaptor Proteins, Signal Transducing, Nuclear Proteins, Prognosis, Autistic Disorder, Amino Acid Sequence, Sequence Homology, Mutation, Missense, Adolescent, Adult, Child, Child, Preschool, Infant, Female, Male, Young Adult, Genetic Association Studies, Intellectual Disability, TRRAP, autism spectrum disorder, congenital malformations, de novo variants, histone acetylation, intellectual disability, neurodevelopmental disorders, Intellectual and Developmental Disabilities (IDD), Pediatric, Genetics, Brain Disorders, Neurosciences, Mental Health, Autism, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Mental health, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Published
2019

12. Return of Results Policies for Genomic Research: Current Practices and the Hearts in Rhythm Organization (HiRO) Approach

Author

Comber, Drake A., Davies, Brianna, Roberts, Jason D., Tadros, Rafik, Green, Martin S., Healey, Jeffrey S., Simpson, Christopher S., Sanatani, Shubhayan, Steinberg, Christian, MacIntyre, Ciorsti, Angaran, Paul, Duff, Henry, Hamilton, Robert, Arbour, Laura, Leather, Richard, Seifer, Colette, Fournier, Anne, Atallah, Joseph, Kimber, Shane, Makanjee, Bhavanesh, Alqarawi, Wael, Cadrin-Tourigny, Julia, Joza, Jacqueline, Gibbs, Karen, Robb, Laura, Zahavich, Laura, Gardner, Martin, Talajic, Mario, Virani, Alice, Krahn, Andrew D., Lehman, Anna, and Laksman, Zachary W.M.

Published
2022
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14. Naturally occurring splice variants dissect the functional domains of BHC80 and emphasize the need for RNA analysis.

Author

Hejla, Duha, Huynh, Stephanie, Samra, Simran, Richmond, Phillip A., Dalmann, Joshua, Del Bel, Kate L., Byres, Loryn, Lehman, Anna, Turvey, Stuart E., and Boerkoel, Cornelius F.

Abstract

Pathogenic PHF21A variation causes PHF21A‐related neurodevelopmental disorders (NDDs). Although amorphic alleles, including haploinsufficiency, have been established as a disease mechanism, increasing evidence suggests that missense variants as well as frameshift variants extending the BHC80 carboxyl terminus also cause disease. Expanding on these, we report a proposita with intellectual disability and overgrowth and a novel de novo heterozygous PHF21A splice variant (NM_001352027.3:c.[153+1G>C];[=]) causing skipping of exon 6, which encodes an in‐frame BHC80 deletion (p.(Asn30_Gln51del)). This deletion disrupts a predicted leucine zipper domain and implicates this domain in BHC80 function and as a target of variation causing PHF21A‐related NDDs. This extension of understanding emphasizes the application of RNA analysis in precision genomic medicine practice. [ABSTRACT FROM AUTHOR]

Published
2024
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15. PIGG variant pathogenicity assessment reveals characteristic features within 19 families

Author

Tremblay-Laganière, Camille, Maroofian, Reza, Nguyen, Thi Tuyet Mai, Karimiani, Ehsan Ghayoor, Kirmani, Salman, Akbar, Fizza, Ibrahim, Shahnaz, Afroze, Bushra, Doosti, Mohammad, Ashrafzadeh, Farah, Babaei, Meisam, Efthymiou, Stephanie, Christoforou, Marilena, Sultan, Tipu, Ladda, Roger L., McLaughlin, Heather M., Truty, Rebecca, Mahida, Sonal, Cohen, Julie S., Baranano, Kristin, Ismail, Fatima Y., Patel, Millan S., Lehman, Anna, Edmondson, Andrew C., Nagy, Amanda, Walker, Melissa A., Mercimek-Andrews, Saadet, Maki, Yuta, Sachdev, Rani, Macintosh, Rebecca, Palmer, Elizabeth E., Mancini, Grazia M. S., Barakat, Tahsin Stefan, Steinfeld, Robert, Rüsch, Christina T., Stettner, Georg M., Wagner, Matias, Wortmann, Saskia B., Kini, Usha, Brady, Angela F., Stals, Karen L., Ismayilova, Naila, Ellard, Sian, Bernardo, Danilo, Nugent, Kimberly, McLean, Scott D., Antonarakis, Stylianos E., Houlden, Henry, Kinoshita, Taroh, Campeau, Philippe M., and Murakami, Yoshiko

Published
2021
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18. FollowME Fabry Pathfinders Registry: Renal effectiveness in a cohort of patients on migalastat treatment for at least three years

Author

West, Michael L., primary, Hughes, Derralynn, additional, Sunder-Plassmann, Gere, additional, Jovanovic, Ana, additional, Brand, Eva, additional, Bichet, Daniel G., additional, Pisani, Antonio, additional, Nowak, Albina, additional, Torra, Roser, additional, Khan, Aneal, additional, Azevedo, Olga, additional, Lehman, Anna, additional, Linhart, Aleš, additional, Rutecki, Jasmine, additional, Giuliano, Joseph D., additional, Krusinska, Eva, additional, and Nordbeck, Peter, additional

Published
2024
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19. Glycosphingolipid evaluation for Fabry disease patients receiving migalastat after switching from enzyme replacement therapy

Author

Auray-Blais, Christiane, primary, Lavoie, Pamela, additional, Martineau, Tristan, additional, Ntumba, Georges Kabala, additional, Gamrani, Mohamed, additional, Khan, Aneal, additional, Altarescu, Gheona, additional, Lehman, Anna, additional, Goker-Alpan, Ozlem, additional, Nowak, Albina, additional, West, Michael L., additional, and Bichet, Daniel G., additional

Published
2024
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21. Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study

Author

Hartley, Taila, primary, Marshall, Deborah, additional, Acker, Meryl, additional, Fooks, Katharine, additional, Gillespie, Meredith K., additional, Price, E. Magda, additional, Graham, Ian D., additional, White-Brown, Alexandre, additional, MacKay, Layla, additional, Macdonald, Stella K., additional, Brady, Lauren, additional, Hui, Angela Y., additional, Andrews, Joseph D., additional, Chowdhury, Ashfia, additional, Wall, Erika, additional, Soubry, Élisabeth, additional, Ediae, Grace U., additional, Rojas, Samantha, additional, Assamad, Daniel, additional, Dyment, David, additional, Tarnopolsky, Mark, additional, Sawyer, Sarah L., additional, Chisholm, Caitlin, additional, Lemire, Gabrielle, additional, Amburgey, Kimberly, additional, Lazier, Joanna, additional, Mendoza-Londono, Roberto, additional, Dowling, James J., additional, Balci, Tugce B., additional, Armour, Christine M., additional, Bhola, Priya T., additional, Costain, Gregory, additional, Dupuis, Lucie, additional, Carter, Melissa, additional, Badalato, Lauren, additional, Richer, Julie, additional, Boswell-Patterson, Christie, additional, Kannu, Peter, additional, Cordeiro, Dawn, additional, Warman-Chardon, Jodi, additional, Graham, Gail, additional, Siu, Victoria Mok, additional, Cytrynbaum, Cheryl, additional, Rusnak, Alison, additional, Aul, Ritu B., additional, Yoon, Grace, additional, Gonorazky, Hernan, additional, McNiven, Vanda, additional, Mercimek-Andrews, Saadet, additional, Guerin, Andrea, additional, Deshwar, Ashish R., additional, Marwaha, Ashish, additional, Weksberg, Rosanna, additional, Karp, Natalya, additional, Campbell, Maggie, additional, Al-Qattan, Sarah, additional, Shuen, Andrew Y., additional, Inbar-Feigenberg, Michal, additional, Cohn, Ronald, additional, Szuto, Anna, additional, Inglese, Cara, additional, Poirier, Myriam, additional, Chad, Lauren, additional, Potter, Beth, additional, Boycott, Kym M., additional, Hayeems, Robin, additional, Boycott, Kym, additional, Brudno, Michael, additional, Bernier, Francois, additional, van Karnebeek, Clara, additional, Kernohan, Kristin, additional, Innes, Micheil, additional, Lamont, Ryan, additional, Parboosingh, Jillian, additional, Marshall, Christian, additional, Mendoza, Roberto, additional, Dowling, James, additional, Knoppers, Bartha, additional, Lehman, Anna, additional, and Mostafavi, Sara, additional

Published
2024
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22. The management and clinical outcomes of pregnancies in women with urea cycle disorders: A review of the literature and results of an international survey

Author

Stepien, Karolina M., primary, Langendonk, Janneke G., additional, Dao, Myriam, additional, Gomes, Daniel Costa, additional, Douillard, Claire, additional, Filipsson, Karin, additional, Glamuzina, Emma, additional, Haverkamp, Jorien A., additional, Langeveld, Mirjam, additional, Lehman, Anna, additional, de Lonlay, Pascale, additional, Lund, Allan M., additional, Oscarson, Mikael, additional, Peltenburg, N. Chantal, additional, Ramadža, Danijela Petković, additional, Ramachandran, Radha, additional, Reismann, Peter, additional, Shtylla, Alboren, additional, Tchan, Michel, additional, Tan, Chong Yew, additional, Wilson, Callum, additional, Woodall, Alison, additional, Murphy, Elaine, additional, and Wagenmakers, Margreet A. E. M., additional

Published
2023
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24. JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Author

Verberne, Eline A., Goh, Shuxiang, England, Jade, van Ginkel, Manon, Rafael-Croes, Louise, Maas, Saskia, Polstra, Abeltje, Zarate, Yuri A., Bosanko, Katherine A., Pechter, Kieran B., Bedoukian, Emma, Izumi, Kosuke, Chaudhry, Ayeshah, Robin, Nathaniel H., Boothe, Megan, Lippa, Natalie C., Aggarwal, Vimla, De Vivo, Darryl C., Lehman, Anna, Study, Causes, Stockler, Sylvia, Bruel, Ange-Line, Isidor, Bertrand, Lemons, Jennifer, Rodriguez-Buritica, David F., Richmond, Christopher M., Stark, Zornitza, Agrawal, Pankaj B., Kooy, R. Frank, Meuwissen, Marije E. C., Koolen, David A., Pfundt, Rolf, Lieden, Agne, Anderlid, Britt-Marie, Glatz, Dagmar, Mannens, Marcel M. A. M., Bakshi, Madhura, Mallette, Frédérick A., van Haelst, Mieke M., and Campeau, Philippe M.

Published
2021
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25. Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic HK1 Variants.

Author

Wortmann, Saskia B., Feichtinger, Rene G., Abela, Lucia, van Gemert, Loes A., Aubart, Mélodie, Dufeu-Berat, Claire-Marine, Boddaert, Nathalie, de Coo, Rene, Stühn, Lara, Hebbink, Jasmijn, Heinritz, Wolfram, Hildebrandt, Julia, Himmelreich, Nastassja, Korenke, Christoph, Lehman, Anna, Leyland, Thomas, Makowski, Christine, Martinez Marin, Rafael Jenaro, Marzin, Pauline, and Mühlhausen, Chris

Published
2024
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26. Fabry disease biomarkers in patients switched from enzyme replacement therapy to migalastat oral chaperone therapy

Author

Auray-Blais, Christiane, primary, Lavoie, Pamela, additional, Martineau, Tristan, additional, Ntumba, Georges Kabala, additional, Gamrani, Mohamed, additional, Khan, Aneal, additional, Altarescu, Gheona, additional, Lehman, Anna, additional, Goker-Alpan, Ozlem, additional, Nowak, Albina, additional, West, Michael L, additional, and Bichet, Daniel G, additional

Published
2023
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27. A germline heterozygous dominant negativeIKZF2variant causing syndromic primary immune regulatory disorder and ICHAD

Author

Lu, Henry Y., primary, Vaseghi-Shanjani, Maryam, additional, Lam, Avery J., additional, Sharma, Mehul, additional, Mohajeri, Arezoo, additional, Gillies, Jana, additional, Yang, Gui Xiang, additional, Lin, Susan, additional, Fu, Maggie P., additional, Salman, Areesha, additional, Rahmanian, Ronak, additional, Armstrong, Linlea, additional, Halparin, Jessica, additional, Yang, Connie L., additional, Chilvers, Mark, additional, Henkelman, Erika, additional, Rehmus, Wingfield, additional, Morrison, Douglas, additional, Setiadi, Audi, additional, Mostafavi, Sara, additional, Kobor, Michael S., additional, Kozak, Frederick K., additional, Biggs, Catherine M., additional, Karnebeek, Clara van, additional, Hildebrand, Kyla J., additional, Lehman, Anna, additional, Levings, Megan K., additional, and Turvey, Stuart E., additional

Published
2023
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29. Increased Ca 2+ Transient Underlies RyR2-Related Left Ventricular Noncompaction

Author

Ni, Mingke, primary, Li, Yanhui, additional, Wei, Jinhong, additional, Song, Zhenpeng, additional, Wang, Hui, additional, Yao, Jinjing, additional, Chen, Yong-Xiang, additional, Belke, Darrell, additional, Estillore, John Paul, additional, Wang, Ruiwu, additional, Vallmitjana, Alexander, additional, Benitez, Raul, additional, Hove-Madsen, Leif, additional, Feng, Wei, additional, Chen, Ju, additional, Roston, Thomas M., additional, Sanatani, Shubhayan, additional, Lehman, Anna, additional, and Chen, S.R. Wayne, additional

Published
2023
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30. Hypogonadotropic Hypogonadism in Males with Glycogen Storage Disease Type 1

Author

Wong, Evelyn M., Lehman, Anna, Acott, Philip, Gillis, Jane, Metzger, Daniel L., Sirrs, Sandra, Baumgartner, Matthias R., Series editor, Patterson, Marc, Series editor, Rahman, Shamima, Series editor, Peters, Verena, Series editor, Morava, Eva, Editor-in-chief, Zschocke, Johannes, Series editor, and Baumgartner, Matthias, editor

Published
2017
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32. RAPIDOMICS: rapid genome-wide sequencing in a neonatal intensive care unit—successes and challenges

Author

Elliott, Alison M., du Souich, Christèle, Lehman, Anna, Guella, Ilaria, Evans, Daniel M., Candido, Tara, Tooman, Leah, Armstrong, Linlea, Clarke, Lorne, Gibson, William, Gill, Harinder, Lavoie, Pascal M., Lewis, Suzanne, McKinnon, Margaret L., Nikkel, Sarah M., Patel, Millan, Solimano, Alfonso, Synnes, Anne, Ting, Joseph, van Allen, Margot, Christilaw, Jan, Farrer, Matthew J., Friedman, Jan M., and Osiovich, Horacio

Published
2019
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35. Generation of tandem alternative splice acceptor sites andCLTChaploinsufficiency: A cause ofCLTC‐related disorder

Author

Sage, Adam P., primary, Lee, Hyun Kyung, additional, Dalmann, Joshua, additional, Lin, Susan, additional, Samra, Simran, additional, Salman, Areesha, additional, Del Bel, Kate L., additional, Li, Wenhui Laura, additional, Lehman, Anna, additional, Turvey, Stuart E., additional, Boerkoel, Cornelius F., additional, and Richmond, Phillip A., additional

Published
2023
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36. Impact of Variation in Practice in the Prenatal Reporting of Variants of Uncertain Significance by Commercial Laboratories: Need for Greater Adherence to Published Guidelines

Author

Cornthwaite, Melissa, primary, Turner, Kelly, additional, Armstrong, Linlea, additional, Boerkoel, Cornelius F., additional, Chang, Caitlin, additional, Lehman, Anna, additional, Nikkel, Sarah M., additional, Patel, Millan S., additional, van Allen, Margot, additional, and Langlois, Sylvie, additional

Published
2023
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37. Dominant Negative Variants in IKZF2 Cause ICHAD Syndrome, a New Disorder Characterized by Immunodysregulation, Craniofacial Anomalies, Hearing Impairment, Athelia, and Developmental Delay

Author

Vaseghi-Shanjani, Maryam, primary, Mohajeri, Arezoo, additional, Rosenfeld, Jill A., additional, Lu, Henry, additional, Sharma, Mehul, additional, Lalani, Seema, additional, Nicholas, Sarah, additional, Scott, Daryl A., additional, Turvey, Stuart, additional, and Lehman, Anna, additional

Published
2023
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38. First reports of primary ciliary dyskinesia caused by a shared DNAH11 allele in Canadian Inuit

Author

Hunter‐Schouela, Julia, primary, Geraghty, Michael T., additional, Hegele, Robert A., additional, Dyment, David A., additional, St Pierre, David, additional, Richer, Julie, additional, Sheffield, Holden, additional, Zariwala, Maimoona A., additional, Knowles, Michael R., additional, Lehman, Anna, additional, Dell, Sharon, additional, Shapiro, Adam J., additional, and Kovesi, Thomas A., additional

Published
2023
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40. NOTCH1loss of the TAD and PEST domain: An antimorph?

Author

Boerkoel, Pierre, primary, Huynh, Stephanie, additional, Yang, Gui Xiang, additional, Boerkoel, Cornelius F., additional, Patel, Millan S., additional, Lehman, Anna, additional, Terry, Jefferson, additional, and Elbert, Adrienne, additional

Published
2023
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44. FollowME Fabry Pathfinders registry: Renal effectiveness in a multi-national, multi-center cohort of patients on migalastat treatment for at least three years

Author

Hughes, Derralynn, primary, Sunder-Plassmann, Gere, additional, Jovanovic, Ana, additional, Brand, Eva, additional, West, Michael L., additional, Bichet, Daniel G., additional, Pisani, Antonio, additional, Nowak, Albina, additional, Torra, Roser, additional, Khan, Aneal, additional, Azevedo, Olga, additional, Lehman, Anna, additional, Rutecki, Jasmine, additional, Giuliano, Joseph D., additional, Krusinska, Eva, additional, and Nordbeck, Peter, additional

Published
2023
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45. Consensus clinical management guidelines for Acid Sphingomyelinase Deficiency (Niemann-Pick disease types A, B and A/B)

Author

Geberhiwot, Tarekegn, primary, Wasserstein, Melissa, additional, Wanninayake, Subadra, additional, Bolton, Shaun Christopher, additional, Dardis, Andrea, additional, Lehman, Anna, additional, Lidove, Oliver, additional, Dawson, Charlotte, additional, Giugliani, Roberto, additional, Imrie, Jackie, additional, Hopkin, Justin, additional, Green, James, additional, Corbeira, Daniel de Vicente, additional, Madathil, Shyam, additional, Mengel, Eugen, additional, Ezgu, Fatih, additional, Pettazzoni, Magali, additional, Sjouke, Barbara, additional, Hollak, Carla, additional, Vanier, Marie T, additional, McGovern, Margaret, additional, and Schuchman, Edward, additional

Published
2022
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48. Generation of tandem alternative splice acceptor sites and CLTC haploinsufficiency: A cause of CLTC‐related disorder.

Author

Sage, Adam P., Lee, Hyun Kyung, Dalmann, Joshua, Lin, Susan, Samra, Simran, Salman, Areesha, Del Bel, Kate L., Li, Wenhui Laura, Lehman, Anna, Turvey, Stuart E., Boerkoel, Cornelius F., and Richmond, Phillip A.

Abstract

Tandem splice acceptors (NAGNnAG) are a common mechanism of alternative splicing, but variants that are likely to generate or to disrupt tandem splice sites have rarely been reported as disease causing. We identify a pathogenic intron 23 CLTC variant (NM_004859.4:c.[3766‐13_3766‐5del];[=]) in a propositus with intellectual disability and behavioral problems. By RNAseq analysis of peripheral blood mRNA, this variant generates transcripts using cryptic proximal splice acceptors (NM_004859.4: r.3765_3766insTTCACAGAAAGGAACTAG, and NM_004859.4:r.3765_3766insAAAGGAACTAG). Given that the propositus expresses 38% the level of CLTC transcripts as unaffected controls, these variant transcripts, which encode premature termination codons, likely undergo nonsense mediated mRNA decay (NMD). This is the first functional evidence for CLTC haploinsufficiency as a cause of CLTC‐related disorder and the first evidence that the generation of tandem alternative splice sites causes CLTC‐related disorder. We suggest that variants creating tandem alternative splice sites are an underreported disease mechanism and that transcriptome‐level analysis should be routinely pursued to define the pathogenicity of such variants. [ABSTRACT FROM AUTHOR]

Published
2023
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49. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.

Author

Karaa, Amel, Bertini, Enrico, Carelli, Valerio, Cohen, Bruce H., Enns, Gregory M., Falk, Marni J., Goldstein, Amy, Gorman, Gráinne Siobhan, Haas, Richard, Hirano, Michio, Klopstock, Thomas, Koenig, Mary Kay, Kornblum, Cornelia, Lamperti, Costanza, Lehman, Anna, Longo, Nicola, Molnar, Maria Judit, Parikh, Sumit, Phan, Han, and Pitceathly, Robert D.S.

Published
2023
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50. NOTCH1 loss of the TAD and PEST domain: An antimorph?

Author

Boerkoel, Pierre, Huynh, Stephanie, Yang, Gui Xiang, Boerkoel, Cornelius F., Patel, Millan S., Lehman, Anna, Terry, Jefferson, and Elbert, Adrienne

Abstract

The Notch proteins play key roles in cell fate determination during development. Germline pathogenic variants in NOTCH1 predispose to a spectrum of cardiovascular malformations including Adams‐Oliver syndrome and a wide variety of isolated complex and simple congenital heart defects. The intracellular C‐terminus of the single‐pass transmembrane receptor encoded by NOTCH1 contains a transcriptional activating domain (TAD) required for target gene activation and a PEST domain (a sequence rich in proline, glutamic acid, serine, and threonine), regulating protein stability and turnover. We present a patient with a novel variant encoding a truncated NOTCH1 protein without the TAD and PEST domain (NM_017617.4: c.[6626_6629del];[=], p.(Tyr2209CysfsTer38)) and extensive cardiovascular abnormalities consistent with a NOTCH1‐mediated mechanism. This variant fails to promote transcription of target genes as assessed by luciferase reporter assay. Given the roles of the TAD and PEST domains in NOTCH1 function and regulation, we hypothesize that loss of both the TAD and the PEST domain results in a stable, loss‐of‐function protein that acts as an antimorph through competition with wild‐type NOTCH1. [ABSTRACT FROM AUTHOR]

Published
2023
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