107 results on '"Elizabeth J, Bhoj"'
Search Results
52. Heterozygous de novo variants in CSNK1G1 are associated with syndromic developmental delay and autism spectrum disorder
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Tim M. Strom, Nina B. Gold, Anna Chassevent, Edward Blair, Lance H. Rodan, Juan Pié, Constance Smith-Hicks, Ilaria Parenti, Feliciano J. Ramos, Maria J. Guillen Sacoto, Kirsty McWalter, Reem Saadeh-Haddad, Elizabeth J. Bhoj, Dong Li, Beatriz Puisac, Frank J. Kaiser, and Hong Cui
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0301 basic medicine ,Adult ,Male ,Heterozygote ,Microarray ,Adolescent ,Autism Spectrum Disorder ,Developmental Disabilities ,Morphogenesis ,Medizin ,030105 genetics & heredity ,Biology ,DNA sequencing ,03 medical and health sciences ,Epilepsy ,Young Adult ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Casein Kinase II ,Child ,Exome ,Genetics (clinical) ,Comparative Genomic Hybridization ,Whole Genome Sequencing ,medicine.disease ,030104 developmental biology ,Autism spectrum disorder ,Child, Preschool ,Autism ,Female ,Comparative genomic hybridization - Abstract
The gamma-1 isoform of casein kinase 1, the protein encoded by CSNK1G1, is involved in the growth and morphogenesis of cells. This protein is expressed ubiquitously among many tissue types, including the brain, where it regulates the phosphorylation of N-methyl-D-aspartate receptors and plays a role in synaptic transmission. One prior individual with a de novo variant in CSNK1G presenting with severe developmental delay and early-onset epilepsy has been reported. Here we report an updated clinical history of this previously published case, as well as four additional individuals with de novo variants in CSNK1G1 identified via microarray-based comparative genomic hybridization, exome, or genome sequencing. All individuals (n = 5) had developmental delay. At least three individuals had diagnoses of autism spectrum disorder. All participants were noted to have dysmorphic facial features, although the reported findings varied widely and therefore may not clearly be recognizable. None of the participants had additional major malformations. Taken together, our data suggest that CSNK1G1 may be a cause of syndromic developmental delay and possibly autism spectrum disorder.
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- 2020
53. Application of exome sequencing to diagnose a novel presentation of the Cornelia de Lange syndrome in an Afro‐Caribbean family
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Sarah H. Elsea, Patrick Z. Carey, Andrew K. Sobering, Beverly Nelson, Maricela A. Ramirez, Janice L. Smith, Wayne Thompson, Dong Li, Elizabeth J. Bhoj, Hakon Hakonarson, John C. Carey, and Tyhiesia Donald
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Adult ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Microcephaly ,Cornelia de Lange Syndrome ,lcsh:QH426-470 ,Cell Cycle Proteins ,Afro-Caribbean ,030105 genetics & heredity ,Clinical Reports ,03 medical and health sciences ,symbols.namesake ,De Lange Syndrome ,Intellectual disability ,Genetics ,medicine ,Humans ,Genetic Testing ,Child ,Molecular Biology ,Genetics (clinical) ,Exome sequencing ,Sanger sequencing ,Caribbean ,Clinical Report ,business.industry ,NIPBL ,medicine.disease ,Cornelia de Lange syndrome ,Pedigree ,lcsh:Genetics ,Phenotype ,030104 developmental biology ,Mutation ,symbols ,Female ,Presentation (obstetrics) ,business ,exome sequencing - Abstract
Background Cornelia de Lange syndrome (CdLS) comprises a recognizable pattern of multiple congenital anomalies caused by variants of the DNA cohesion complex. Affected individuals may display a wide range of phenotypic severity, even within the same family. Methods Exome sequencing and confirmatory Sanger sequencing showed the same previously described p.Arg629Ter NIPBL variant in two half‐brothers affected with CdLS. Clinical evaluations were obtained in a pro bono genetics clinic. Results One brother had relatively mild proportionate limb shortening; the other had complete bilateral hypogenesis of the upper arm with absence of lower arm structures, terminal transverse defects, and no digit remnants. His complex lower limb presentation included long bone deficiency and a deviated left foot. The mother had intellectual disability and microcephaly but lacked facial features diagnostic of the CdLS. Conclusion We describe a collaboration between a pediatrics team from a resource‐limited nation and USA‐based medical geneticists. Reports describing individuals of West Indian ancestry are rarely found in the medical literature. Here, we present a family of Afro‐Caribbean ancestry with CdLS presenting with phenotypic variability, including unusual lower limb abnormalities. The observation of this novel family adds to our knowledge of the phenotypic and molecular aspects of CdLS., We found the same pathogenic NIPBL variant in two half‐brothers who are of Afro‐Caribbean ancestry. One of the brothers has a novel lower limb presentation.
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- 2020
54. Histone H3.3 beyond cancer: Germline mutations in
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Laura, Bryant, Dong, Li, Samuel G, Cox, Dylan, Marchione, Evan F, Joiner, Khadija, Wilson, Kevin, Janssen, Pearl, Lee, Michael E, March, Divya, Nair, Elliott, Sherr, Brieana, Fregeau, Klaas J, Wierenga, Alexandrea, Wadley, Grazia M S, Mancini, Nina, Powell-Hamilton, Jiddeke, van de Kamp, Theresa, Grebe, John, Dean, Alison, Ross, Heather P, Crawford, Zoe, Powis, Megan T, Cho, Marcia C, Willing, Linda, Manwaring, Rachel, Schot, Caroline, Nava, Alexandra, Afenjar, Davor, Lessel, Matias, Wagner, Thomas, Klopstock, Juliane, Winkelmann, Claudia B, Catarino, Kyle, Retterer, Jane L, Schuette, Jeffrey W, Innis, Amy, Pizzino, Sabine, Lüttgen, Jonas, Denecke, Tim M, Strom, Kristin G, Monaghan, Zuo-Fei, Yuan, Holly, Dubbs, Renee, Bend, Jennifer A, Lee, Michael J, Lyons, Julia, Hoefele, Roman, Günthner, Heiko, Reutter, Boris, Keren, Kelly, Radtke, Omar, Sherbini, Cameron, Mrokse, Katherine L, Helbig, Sylvie, Odent, Benjamin, Cogne, Sandra, Mercier, Stephane, Bezieau, Thomas, Besnard, Sebastien, Kury, Richard, Redon, Karit, Reinson, Monica H, Wojcik, Katrin, Õunap, Pilvi, Ilves, A Micheil, Innes, Kristin D, Kernohan, Gregory, Costain, M Stephen, Meyn, David, Chitayat, Elaine, Zackai, Anna, Lehman, Hilary, Kitson, Martin G, Martin, Julian A, Martinez-Agosto, Stan F, Nelson, Christina G S, Palmer, Jeanette C, Papp, Neil H, Parker, Janet S, Sinsheimer, Eric, Vilain, Jijun, Wan, Amanda J, Yoon, Allison, Zheng, Elise, Brimble, Giovanni Battista, Ferrero, Francesca Clementina, Radio, Diana, Carli, Sabina, Barresi, Alfredo, Brusco, Marco, Tartaglia, Jennifer Muncy, Thomas, Luis, Umana, Marjan M, Weiss, Garrett, Gotway, K E, Stuurman, Michelle L, Thompson, Kirsty, McWalter, Constance T R M, Stumpel, Servi J C, Stevens, Alexander P A, Stegmann, Kristian, Tveten, Arve, Vøllo, Trine, Prescott, Christina, Fagerberg, Lone Walentin, Laulund, Martin J, Larsen, Melissa, Byler, Robert Roger, Lebel, Anna C, Hurst, Joy, Dean, Samantha A, Schrier Vergano, Jennifer, Norman, Saadet, Mercimek-Andrews, Juanita, Neira, Margot I, Van Allen, Nicola, Longo, Elizabeth, Sellars, Raymond J, Louie, Sara S, Cathey, Elly, Brokamp, Delphine, Heron, Molly, Snyder, Adeline, Vanderver, Celeste, Simon, Xavier, de la Cruz, Natália, Padilla, J Gage, Crump, Wendy, Chung, Benjamin, Garcia, Hakon H, Hakonarson, and Elizabeth J, Bhoj
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endocrine system ,SciAdv r-articles ,Forkhead Transcription Factors ,Neurodegenerative Diseases ,Zebrafish Proteins ,Histones ,fluids and secretions ,mental disorders ,Genetics ,Animals ,Humans ,Molecular Biology ,reproductive and urinary physiology ,Germ-Line Mutation ,Zebrafish ,Research Articles ,Research Article - Abstract
Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome., 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.
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- 2020
55. Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities
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Yoel Hirsch, Martin Jakob Larsen, Patrick Rump, Elaine H. Zackai, Jennifer L. Cohen, Sarah E Sheppard, Alison M. Muir, David A. Zeevi, Heather C Mefford, Tsz Y. Lo, Natalie Weed, Yuanquan Song, Lars Kjærsgaard, Elizabeth J. Bhoj, Christina Fagerberg, Pavithran Guttipatti, Dan Doherty, Katharina Löhner, and Danielle DeMarzo
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Male ,Microcephaly ,Pathology ,Disease ,0302 clinical medicine ,Loss of Function Mutation ,Medicine ,Drosophila Proteins ,Eye Abnormalities ,Nuclear pore ,Genetics (clinical) ,0303 health sciences ,education.field_of_study ,Brain ,Syndrome ,beta Karyopherins ,Phenotype ,Hypotonia ,DROSOPHILA ,Drosophila melanogaster ,Child, Preschool ,Congenital cataracts ,Female ,medicine.symptom ,NUCLEAR-PORE ,Heart Defects, Congenital ,medicine.medical_specialty ,GENES ,Population ,Active Transport, Cell Nucleus ,Genes, Recessive ,Article ,MECHANISMS ,03 medical and health sciences ,Seizures ,Genetics ,Animals ,Humans ,education ,Alleles ,030304 developmental biology ,Cell Nucleus ,MUTATIONS ,business.industry ,Infant, Newborn ,Infant ,Dendrites ,Fibroblasts ,medicine.disease ,Nuclear Pore Complex Proteins ,Jews ,business ,030217 neurology & neurosurgery ,Ventriculomegaly - Abstract
Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype.
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- 2020
56. EP300-related Rubinstein-Taybi syndrome: Highlighted rare phenotypic findings and a genotype-phenotype meta-analysis of 74 patients
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Samantha A. Schrier Vergano, Victoria Zurcher, Emma Bedoukian, Ian D. Krantz, Amber Hoffman, Carey McDougall, Kosuke Izumi, Beth Keena, Elizabeth J. Bhoj, Alyssa Ritter, Jennifer L. Cohen, Elaine H. Zackai, Matthew A. Deardorff, Alanna Strong, Dong Li, Sarah Mazzola, and Leah W. Burke
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0301 basic medicine ,Male ,Adolescent ,Disease ,030105 genetics & heredity ,Biology ,Cohort Studies ,03 medical and health sciences ,Intellectual disability ,Genetics ,medicine ,Humans ,EP300 ,Child ,Genetics (clinical) ,Genetic Association Studies ,Rubinstein-Taybi Syndrome ,Rubinstein–Taybi syndrome ,Infant ,medicine.disease ,Prognosis ,Phenotype ,030104 developmental biology ,Child, Preschool ,Mutation ,Female ,Imperforate anus ,Haploinsufficiency ,E1A-Associated p300 Protein ,Rare disease - Abstract
Pathogenic variants in the homologous and highly conserved genes-CREBBP and EP300-are causal for Rubinstein-Taybi syndrome (RSTS). CREBBP and EP300 encode histone acetyltransferases (HAT) that act as transcriptional co-activators, and their haploinsufficiency causes the pathology characteristic of RSTS by interfering with global transcriptional regulation. Though generally a well-characterized syndrome, there is a clear phenotypic spectrum; rare associations have emerged with increasing diagnosis that is critical for comprehensive understanding of this rare syndrome. We present 12 unreported patients with RSTS found to have EP300 variants discovered through gene sequencing and chromosomal microarray. Our cohort highlights rare phenotypic features associated with EP300 variants, including imperforate anus, retained fetal finger pads, and spina bifida occulta. Our findings support the previously noted prevalence of pregnancy-related hypertension/preeclampsia seen with this disease. We additionally performed a meta-analysis on our newly reported 12 patients and 62 of the 90 previously reported patients. We demonstrated no statistically significant correlation between phenotype severity (within the domains of intellectual disability and major organ involvement, as defined in our Methods section) and variant location and type; this is in contrast to the conclusions of some smaller studies and highlights the importance of large patient cohorts in characterization of this rare disease.
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- 2020
57. De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay
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Paul Kruszka, Sreehari Kalvakuri, Austin Larson, Dong Li, Inge van Outersterp, Florence Demurger, Ian Hayes, F. Lucy Raymond, Lauren J. Massingham, Claudia A. L. Ruivenkamp, Ian D. Krantz, Kendra Brunet, Nicole Revencu, Maaike Vreeburg, Donatella Milani, Tjitske Kleefstra, Lisenka E.L.M. Vissers, Maximilian Muenke, Sinje Geuer, Candace Gamble, Rolf Bodmer, Hanka Venselaar, Elke de Boer, Sarina G. Kant, Dilys Weijers, Arjan P.M. de Brouwer, Machteld M. Oud, Maria Iascone, Christopher C. Griffith, Frédéric Tran Mau-Them, Karin Weiss, Megan T. Cho, Ayesha Ahmad, James A. Bartley, Nina Powell Hamilton, Lenika De Simone, George E. Hoganson, Lucie Evenepoel, Simone Kersten, Daniel L. Polla, Himanshu Goel, Antonio Vitobello, Rachel Fisher, Arthur Sorlin, Sébastien Moutton, Myrthe van den Born, Hilary J. Vernon, Michael Kwint, Kaitlyn Burns, Anna Ruiz, Kirsty McWalter, Jenny Morton, Jennifer Schwab, Elizabeth J. Bhoj, Philippe Christophe, Hans van Bokhoven, Elisabeth Gabau, Kimberly M. Nugent, Jill R. Murrell, Thierry Billette de Villemeur, Kathleen Wood, Alexandra Afenjar, Amber Begtrup, Chanika Phornphutkul, Sarah E. Raible, Melde Witmond, Perrine Charles, Claudia Soler-Alfonso, D. Isum Ward, Marjolaine Willems, Boris Keren, Julian Delanne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Clinical Genetics, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Polikliniek (9)
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Male ,DYRK1A ,Developmental Disabilities ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Gene Expression ,de novo mutations ,Haploinsufficiency ,0302 clinical medicine ,Gene expression ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,Genetics (clinical) ,Genetics ,0303 health sciences ,Gene knockdown ,repressor ,neurodevelopment ,Protein Stability ,CCR4-NOT complex ,Phenotype ,developmental delay ,intellectual disability ,Drosophila ,deadenylase complex ,Female ,regulators ,Heterozygote ,Receptors, CCR4 ,Biology ,Nervous System Malformations ,03 medical and health sciences ,Report ,genomics ,Humans ,Gene ,Alleles ,030304 developmental biology ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Genetic Variation ,Protein ubiquitination ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Neurodevelopmental Disorders ,SUBUNIT ,RNA ,CNOT1 ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,exome sequencing ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Contains fulltext : 220423.pdf (Publisher’s version ) (Closed access) CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.
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- 2020
58. Expanding the clinical and phenotypic heterogeneity associated with biallelic variants in ACO2
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Samantha A. Schrier Vergano, Amy Kenney, Carrie A. Lahner, Mais Hashem, Deborah L. Renaud, Niema Ibrahim, Brendan C. Lanpher, Mohammed Zain Seidahmed, Patrick R. Blackburn, Elizabeth J. Bhoj, Dong Li, Linda Hasadsri, Matthew J. Schultz, Fowzan S. Alkuraya, and Laura J. Fisher
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0301 basic medicine ,Adult ,Male ,Ataxia ,Adolescent ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Bioinformatics ,Compound heterozygosity ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Retinitis pigmentosa ,medicine ,Humans ,RC346-429 ,Child ,Cerebellar hypoplasia ,Research Articles ,Episodic ataxia ,Aconitate Hydratase ,business.industry ,Genetic heterogeneity ,General Neuroscience ,Infant ,medicine.disease ,Pedigree ,030104 developmental biology ,Phenotype ,Disease Presentation ,Female ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,medicine.symptom ,Nervous System Diseases ,business ,030217 neurology & neurosurgery ,RC321-571 ,Research Article - Abstract
Objective We describe the clinical characteristics and genetic etiology of several new cases within the ACO2‐related disease spectrum. Mitochondrial aconitase (ACO2) is a nuclear‐encoded tricarboxylic acid cycle enzyme. Homozygous pathogenic missense variants in the ACO2 gene were initially associated with infantile degeneration of the cerebrum, cerebellum, and retina, resulting in profound intellectual and developmental disability and early death. Subsequent studies have identified a range of homozygous and compound heterozygous pathogenic missense, nonsense, frameshift, and splice‐site ACO2 variants in patients with a spectrum of clinical manifestations and disease severities. Methods We describe a cohort of five novel patients with biallelic pathogenic variants in ACO2. We review the clinical histories of these patients as well as the molecular and functional characterization of the associated ACO2 variants and compare with those described previously in the literature. Results Two siblings with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities including hyperactivity and depressive symptoms with generalized anxiety. One patient presented with the classic form with cerebellar hypoplasia, ataxia, seizures, optic atrophy, and retinitis pigmentosa. Another unrelated patient presented with ataxia but developed severe progressive spastic quadriplegia. Another patient demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. Interpretation In this study, we highlight the importance of recognizing milder forms of the disorder, which may escape detection due to atypical disease presentation.
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- 2020
59. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients
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Thomas Besnard, Kristian Tveten, Hilary F Kitson, Jennifer A. Lee, Brieana Fregeau, Rachel Schot, Khadija Wilson, Katrin Õunap, Juliane Winkelmann, Anna Lehman, Nicola Longo, Servi J. C. Stevens, Megan T. Cho, Christina G.S. Palmer, Causes Study, Giovanni Battista Ferrero, Joy Dean, Lone W. Laulund, Grazia M.S. Mancini, Matias Wagner, Martin G. Martin, Sabine Lüttgen, Elizabeth J. Bhoj, Amanda J. Yoon, Thomas Klopstock, Janet S. Sinsheimer, Eric Vilain, Sébastien Küry, Francesca Clementina Radio, Jiddeke M. van de Kamp, Cameron Mrokse, Hakon Hakonarson, Samuel G. Cox, Jeanette C. Papp, Margot I. Van Allen, Raymond J. Louie, Constance T. R. M. Stumpel, Evan F. Joiner, Juanita Neira, Arve Vøllo, Amy Pizzino, Kelly Radtke, Celeste Simon, Michelle L. Thompson, Allison Zheng, Omar Sherbini, Marcia C. Willing, Tim M. Strom, Benjamin Garcia, Sara S. Cathey, Theresa A. Grebe, Dong Li, Marjan M. Weiss, Marco Tartaglia, Laura M Bryant, Sandra Mercier, Katherine L. Helbig, Martin Jakob Larsen, Ddd Study, Alexandrea Wadley, Alexander P.A. Stegmann, Sabina Barresi, A. Micheil Innes, Elaine H. Zackai, Gregory Costain, Davor Lessel, Molly Snyder, Heather P. Crawford, Richard Redon, Pearl Lee, Melissa Byler, Holly Dubbs, J. Gage Crump, K. E. Stuurman, Boris Keren, Stéphane Bézieau, Stan F. Nelson, Kristin G. Monaghan, Michael J. Lyons, Jeffrey W. Innis, Anna C.E. Hurst, Elizabeth A. Sellars, Samantha A. Schrier Vergano, Saadet Mercimek-Andrews, Monica H. Wojcik, Alison Ross, Heiko Reutter, Zuo-Fei Yuan, Dylan M. Marchione, Renee Bend, Diana Carli, Zöe Powis, Neil H. Parker, Jennifer Muncy Thomas, Luis A. Umaña, Adeline Vanderver, Julia Hoefele, Linda Manwaring, Christina Fagerberg, Elly Brokamp, M. Stephen Meyn, Pilvi Ilves, Xavier de la Cruz, Nina Powell-Hamilton, Caroline Nava, Garrett Gotway, Karit Reinson, Kristin D. Kernohan, Jennifer Norman, Alexandra Afenjar, Benjamin Cogné, Delphine Héron, Roman Günthner, Alfredo Brusco, John Dean, Kevin A. Janssen, Robert Roger Lebel, Divya Nair, Jijun Wan, Julian A. Martinez-Agosto, Elliott H. Sherr, Kyle Retterer, Claudia B. Catarino, Michael E. March, Natalia Padilla, Elise Brimble, Sylvie Odent, Jane L. Schuette, David Chitayat, Klaas J. Wierenga, Kirsty McWalter, Trine Prescott, Jonas Denecke, Wendy K. Chung, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), and Clinical Genetics
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metabolism [Zebrafish Proteins] ,RESIDUE ,metabolism [Histones] ,GENES ,Somatic cell ,CODE ,cancer mutation ,histone ,Biology ,VARIANTS ,medicine.disease_cause ,progressive neurologic dysfunction ,Histones ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,Germline mutation ,SDG 3 - Good Health and Well-being ,histone, neurodevelopmental disorder, progressive neurologic dysfunction, congenital anomalies, cancer mutation ,medicine ,Animals ,Humans ,H3-3A protein, human ,metabolism [Zebrafish] ,TRANSCRIPTION ,PHOSPHORYLATION ,Gene ,Zebrafish ,Germ-Line Mutation ,030304 developmental biology ,Genetics ,genetics [Zebrafish] ,0303 health sciences ,Multidisciplinary ,foxd3 protein, zebrafish ,congenital anomalies ,Forkhead Transcription Factors ,Zebrafish Proteins ,biology.organism_classification ,genetics [Histones] ,neurodevelopmental disorder ,H3F3B ,Histone ,genetics [Forkhead Transcription Factors] ,genetics [Neurodegenerative Diseases] ,biology.protein ,ddc:500 ,Carcinogenesis ,030217 neurology & neurosurgery - Abstract
Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome. 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
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- 2020
60. Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants
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Jennifer Tarpinian, Alberto Fernández-Jaén, Deborah A. Nickerson, Michael J. Bamshad, Kosuke Izumi, Giovanni Battista Ferrero, Emma Bedoukian, Marcello Niceta, Brendan Lee, A. Micheil Innes, Yuri A. Zarate, Katherine A. Bosanko, Annie Laquerrière, Jennifer A. Bassetti, David Mowat, Beth Keena, Carolina Galaz-Montoya, Claudia Gonzaga-Jauregui, Boris Keren, Reid Sutton, Elaine H. Zackai, James R. Lupski, Constance F. Wells, Francesca Clementina Radio, Natalie Hauser, Dong Li, Grace U Ediae, Marco Tartaglia, Xiang-Jiao Yang, Para Chottil Soumya, Elizabeth J. Bhoj, Christine Coubes, Kinattinkara R. Subbaraman, Alain Verloes, Klaus Dieterich, John C. Carey, Mary K. Kukolich, Francisco Cammarata-Scalisi, Alper Gezdirici, Jessica X. Chong, Sirinart Molidperee, Amelle Shillington, Sarah L. Sawyer, David S. Liu, Ana Bracho, Li Xin Zhang, Richard A. Gibbs, Sheela Nampoothiri, Ingrid A. Holm, Philip M. Boone, Alyssa Ritter, Charlotte Dubucs, Philippe M. Campeau, Gabrielle Lemire, Maria Lisa Dentici, Jacqueline Aziza, Frank J. Probst, Karippoth Mohandas Nair, Millan S. Patel, and Chester W. Brown
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0301 basic medicine ,Say–Barber–Biesecker–Young–Simpson syndrome ,030105 genetics & heredity ,Blepharophimosis ,Bioinformatics ,KAT6B ,Article ,03 medical and health sciences ,genitopatellar syndrome ,KAT6B disorders ,SBBYSS ,Intellectual Disability ,Genotype ,Medicine ,Humans ,Allele ,Increased nuchal translucency ,Genetics (clinical) ,Histone Acetyltransferases ,Optic nerve hypoplasia ,Polydactyly ,business.industry ,Enfermedades genéticas congénitas ,Pediatría ,Embriología ,Cystic hygroma ,Exons ,medicine.disease ,Genética ,030104 developmental biology ,Intestinal malrotation ,Mutation ,Genitopatellar syndrome ,business - Abstract
Purpose :Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusión: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals. Sin financiación 8.822 JCR(2020) Q1, 15/176 Genetics & Heredity 3.509 SJR (2020) Q1, 7/96 Genetics (clinical) No data IDR 2020 UEM
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- 2020
61. An Algorithm for the Assessment of Facial Asymmetry in Children With Focus on Etiology and Treatment
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Elizabeth J. Bhoj, Tara L. Wenger, and Emily R. Gallagher
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Pediatrics ,medicine.medical_specialty ,Referral ,business.industry ,030206 dentistry ,03 medical and health sciences ,0302 clinical medicine ,Facial Asymmetry ,Otorhinolaryngology ,Etiology ,medicine ,Humans ,Oral Surgery ,Craniofacial ,Child ,030223 otorhinolaryngology ,business ,Algorithms ,Facial symmetry - Abstract
Background: Facial asymmetry is a common referral indication for craniofacial teams but has a wide range of causes. Prompt identification of etiology is critical to treatment, as medical and surgical interventions vary depending on the cause of asymmetry in each patient. Solution: A standardized diagnostic algorithm. What We Did That Is New: We developed an algorithm to assist in the diagnostic evaluation of facial asymmetry with a focus on next steps for medically actionable causes.
- Published
- 2018
62. Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data
- Author
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Alisha Wilkens, Ian D. Krantz, Laura K. Conlin, Mahdi Sarmady, Nancy B. Spinner, Addie I. Nesbitt, Zhenming Yu, Elizabeth J. Bhoj, Eric D. Marsh, Dimitri S. Monos, Elizabeth Denenberg, Peter White, Chao Wu, Jeffrey W. Pennington, Xiangdong Zhou, Kajia Cao, Avni Santani, Matt Deardorff, Emma Bedoukian, Qiaoning Guan, Bo Zhang, Holly Dubbs, Elaine H. Zackai, Kristin McDonald Gibson, Elizabeth T. DeChene, Minjie Luo, and Livija Medne
- Subjects
0301 basic medicine ,Genomic data ,Zhàng ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,Computational biology ,Polymorphism, Single Nucleotide ,Sensitivity and Specificity ,Validation testing ,03 medical and health sciences ,INDEL Mutation ,Data accuracy ,Humans ,Exome ,Genetic Predisposition to Disease ,Genetic Testing ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Genetic Association Studies ,Genetics (clinical) ,Genetics ,Interpretation (philosophy) ,Computational Biology ,High-Throughput Nucleotide Sequencing ,Reproducibility of Results ,Genomics ,Sequence Analysis, DNA ,Data Accuracy ,030104 developmental biology ,ComputingMethodologies_GENERAL ,Psychology - Abstract
PurposeThe objective of this study was to assess the ability of our laboratory's exome-sequencing test to detect known and novel sequence variants and identify the critical factors influencing the interpretation of a clinical exome test.MethodsWe developed a two-tiered validation strategy: (i) a method-based approach that assessed the ability of our exome test to detect known variants using a reference HapMap sample, and (ii) an interpretation-based approach that assessed our relative ability to identify and interpret disease-causing variants, by analyzing and comparing the results of 19 randomly selected patients previously tested by external laboratories.ResultsWe demonstrate that this approach is reproducible with99% analytical sensitivity and specificity for single-nucleotide variants and indels10 bp. Our findings were concordant with the reference laboratories in 84% of cases. A new molecular diagnosis was applied to three cases, including discovery of two novel candidate genes.ConclusionWe provide an assessment of critical areas that influence interpretation of an exome test, including comprehensive phenotype capture, assessment of clinical overlap, availability of parental data, and the addressing of limitations in database updates. These results can be used to inform improvements in phenotype-driven interpretation of medical exomes in clinical and research settings.
- Published
- 2018
63. Contribution of Mendelian disorders in an unbiased pediatric neurodegeneration cohort
- Author
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Erin Will, Elizabeth J. Bhoj, Frank D. Mentch, Rose Guo, and Rebecca C. Ahrens-Nicklas
- Subjects
Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Neurodegeneration ,Cohort ,Genetics ,Medicine ,Bioinformatics ,business ,medicine.disease ,Molecular Biology ,Biochemistry ,Mendelian disorders - Published
- 2021
64. Microcephaly in an Afro-Caribbean individual with an apparent de novo variant in TUBG1
- Author
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Andrew E. Timms, Andrew K. Sobering, Tyhiesia Donald, Mohamed Idries, Elizabeth J. Bhoj, and Ghayda M. Mirzaa
- Subjects
Genetics ,Microcephaly ,Endocrinology ,Endocrinology, Diabetes and Metabolism ,medicine ,Afro-Caribbean ,Biology ,medicine.disease ,Molecular Biology ,Biochemistry - Published
- 2021
65. Contemporary Evaluation of the Neonate with Congenital Anomalies
- Author
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Tara L. Wenger and Elizabeth J. Bhoj
- Subjects
medicine.medical_specialty ,Assisted reproductive technology ,biology ,business.industry ,medicine.medical_treatment ,Context (language use) ,Reproductive technology ,biology.organism_classification ,Terminology ,Zika virus ,03 medical and health sciences ,0302 clinical medicine ,Prenatal screening ,030225 pediatrics ,Pediatrics, Perinatology and Child Health ,Medicine ,030212 general & internal medicine ,Family history ,business ,Intensive care medicine ,Exome sequencing - Abstract
The evaluation of the neonate with congenital anomalies has always been a vital and challenging task. In recent years, many advances and challenges have complicated the process, including noninvasive prenatal screening, Zika virus, assisted reproductive technology, and rapid exome sequencing. This review will provide a context for the general evaluation of a neonate with congenital anomalies, including adaptation of the most precise terminology, definition of major and minor anomalies, and the determination of whether the anomalies are the result of a sequence, deformation, disruption, or malformation. Practical tools, including a concise family history, nutritional implication, pregnancy history, and the effects of assisted reproductive technologies are also presented. With the advent of Zika virus–associated congenital anomalies, emphasis has also been placed on travel and infection exposures. A particular challenge has been the incorporation of both pre- and postnatal genetic screening and testing into a diagnostic framework. The most common tests will be reviewed, including the practical applications of both a positive and negative result in varying contexts. It has become clear that noninvasive prenatal screening and rapid exome sequencing are having an increasing impact on the evaluation of children with congenital anomalies, and their application and evaluation of their results will be reviewed in detail. The overarching goal of this review is to provide neonatal clinicians the tools to assess, contextualize, and discuss congenital anomalies in neonates to improve communication and the diagnostic process.
- Published
- 2017
66. Phenotypic predictors and final diagnoses in patients referred for RASopathy testing by targeted next-generation sequencing
- Author
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Zhenming Yu, Matthew A. Deardorff, Avni Santani, Kajia Cao, Rebecca C. Ahrens-Nicklas, Minjie Luo, Tanya Tischler, Qiaoning Guan, Elizabeth J. Bhoj, and Elaine H. Zackai
- Subjects
0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,MAP Kinase Signaling System ,Physical examination ,030105 genetics & heredity ,RASopathy ,Negative Test Result ,Article ,03 medical and health sciences ,Costello syndrome ,LEOPARD Syndrome ,Humans ,Medicine ,Medical diagnosis ,Genetics (clinical) ,Retrospective Studies ,Genetic testing ,medicine.diagnostic_test ,business.industry ,Costello Syndrome ,Noonan Syndrome ,High-Throughput Nucleotide Sequencing ,medicine.disease ,Phenotype ,030104 developmental biology ,ras Proteins ,Noonan syndrome ,Differential diagnosis ,business - Abstract
RASopathies include disorders generally characterized by developmental delay, specific heart defects, short stature, cardiac hypertrophy, and facial dysmorphisms. Next-generation sequencing (NGS)-based panels have widespread acceptance as a diagnostic tool for RASopathies. The first 126 patients evaluated by clinical examination and the NGS RASopathy panel at the Children’s Hospital of Philadelphia were enrolled. We calculated diagnosis rate, correlated reported clinical findings with positive or negative test results, and identified final molecular diagnoses in 28/96 patients who tested negative for RASopathies. Twenty-four patients had pathogenic variants on the RASopathy panel, for a diagnostic yield of 19%. Reported features of pulmonic stenosis and ptosis were significantly correlated with a positive test result; no reported features were significantly correlated with a negative test result. We identified 27 different alternative diagnoses for patients originally suspected of having RASopathies. This study provides information that can assist in guiding differential diagnosis and genetic testing for patients suspected of having a RASopathy disorder. Genet Med advance online publication 20 October 2016
- Published
- 2017
67. An Additional Individual with a De Novo Variant in Myelin Regulatory Factor ( MYRF) with Cardiac and Urogenital Anomalies: Further Proof of Causality: Comments on the article by Pinz et al. ()
- Author
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Marjan M. Nezarati, Rhonda E. Schnur, David Chitayat, Tami Uster, Elizabeth J. Bhoj, and Patrick Shannon
- Subjects
0301 basic medicine ,business.industry ,Genitourinary system ,Myelin regulatory factor ,Urogenital Abnormality ,Bioinformatics ,Causality ,03 medical and health sciences ,030104 developmental biology ,Genetics ,Medicine ,business ,Transcription factor ,Genetics (clinical) - Published
- 2018
68. What not to expect when you're expecting: Unusual cases of placental mosaicism detected on non-invasive prenatal screening
- Author
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Maeve K. Hopkins, Erica Schindewolf, Elizabeth J. Bhoj, Katheryn Grand, Lorraine Dugoff, and Amanda Barone Pritchard
- Subjects
Adult ,Pregnancy ,medicine.medical_specialty ,business.industry ,Obstetrics ,Mosaicism ,Placenta ,Non invasive ,MEDLINE ,Prenatal diagnosis ,General Medicine ,medicine.disease ,Chromosomes ,Trophoblasts ,Prenatal screening ,Prenatal Diagnosis ,Genetics ,Medicine ,Humans ,Female ,business ,Cell-Free Nucleic Acids ,Genetics (clinical) - Published
- 2019
69. Generalized, severe epidermolysis bullosa simplex caused by a Keratin 5 p.E477K mutation
- Author
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Leslie Castelo-Soccio, Elizabeth J. Bhoj, Cathryn Sibbald, Marissa J. Perman, Colleen H. Cotton, Laura Elizabeth Anderson, and Sarah E Sheppard
- Subjects
Pathology ,medicine.medical_specialty ,macromolecular substances ,Dermatology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Epidermolysis bullosa simplex ,0302 clinical medicine ,Skin fragility ,medicine ,Humans ,Point Mutation ,integumentary system ,business.industry ,Infant ,medicine.disease ,Keratin 5 ,Epidermis (zoology) ,030220 oncology & carcinogenesis ,Epidermolysis Bullosa Simplex ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,Keratin-5 ,Female ,Epidermolysis bullosa ,business - Abstract
Epidermolysis bullosa simplex (EBS) is a skin fragility disorder resulting from mutations of structural proteins in the epidermis. We provide a brief report of long-term survival and reproduction in a mother with EBS due to keratin 5 (KRT5) c.1429G > A (p.E477K) mutation, which causes a particularly severe form of the disease.
- Published
- 2019
70. Mapping RNA splicing variations in clinically-accessible and non-accessible tissues to facilitate Mendelian disease diagnosis using RNA-seq
- Author
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Yoseph Barash, Jorge Vaquero-Garcia, Joseph K. Aicher, Elizabeth J. Bhoj, and Paul Jewell
- Subjects
0303 health sciences ,CATS ,Sequence Analysis, RNA ,Gene Expression Profiling ,RNA Splicing ,Alternative splicing ,Fetal tissue ,RNA ,RNA-Seq ,Computational biology ,Biology ,Mendelian disease ,Human genetics ,Article ,DNA sequencing ,Alternative Splicing ,03 medical and health sciences ,0302 clinical medicine ,Exome Sequencing ,RNA splicing ,Gene ,Genetics (clinical) ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
PurposeRNA-seq is a promising approach to improve diagnoses by detecting pathogenic aberrations in RNA splicing that are missed by DNA sequencing. RNA-seq is typically performed on clinically-accessible tissues (CATs) from blood and skin. RNA tissue-specificity makes it difficult to identify aberrations in relevant but non-accessible tissues (non-CATs). We determined how RNA-seq from CATs represent splicing in and across genes and non-CATs.MethodsWe quantified RNA splicing in 801 RNA-seq samples from 56 different adult and fetal tissues from GTEx and ArrayExpress. We identified genes and splicing events in each non-CAT and determined when RNA-seq in each CAT would inadequately represent them. We developed an online resource, MAJIQ-CAT, for exploring our analysis for specific genes and tissues.ResultsIn non-CATs, 39.7% of genes have splicing that is inadequately represented by at least one CAT. 6.2% of genes have splicing inadequately represented by all CATs. A majority (52.8%) of inadequately represented genes are lowly expressed in CATs (TPM < 1), but 6.2% are inadequately represented despite being well expressed (TPM > 10).ConclusionMany splicing events in non-CATs are inadequately evaluated using RNA-seq from CATs. MAJIQ-CAT allows users to explore which accessible tissues, if any, best represent splicing in genes and tissues of interest.
- Published
- 2019
71. Muenke syndrome: Medical and surgical comorbidities and long‐term management
- Author
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Elaine H. Zackai, Bridget M. Stroup, Chaya N. Murali, Scott P. Bartlett, Sarah E Sheppard, Tara L. Wenger, Donna M. McDonald-McGinn, Jesse A. Taylor, Carey McDougall, Avni Santani, and Elizabeth J. Bhoj
- Subjects
Adult ,Male ,Proband ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Autism Spectrum Disorder ,Hearing loss ,Osteogenesis, Distraction ,Gene Expression ,Comorbidity ,Article ,Muenke syndrome ,Craniosynostosis ,Cohort Studies ,Craniosynostoses ,Recurrence ,Genetics ,medicine ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Otitis ,Child ,Hearing Loss ,Genetics (clinical) ,Philadelphia ,Coronal craniosynostosis ,business.industry ,Disease Management ,Synostosis ,medicine.disease ,Middle Ear Ventilation ,Pedigree ,Autism spectrum disorder ,Child, Preschool ,Mutation ,Female ,medicine.symptom ,business - Abstract
Muenke syndrome (MIM #602849), the most common syndromic craniosynostosis, results from the recurrent pathogenic p.P250R variant in FGFR3. Affected patients exhibit wide phenotypic variability. Common features include coronal craniosynostosis, hearing loss, carpal and tarsal anomalies, and developmental/behavioral issues. Our study examined the phenotypic findings, medical management, and surgical outcomes in a cohort of 26 probands with Muenke syndrome identified at the Children’s Hospital of Philadelphia. All probands had craniosynostosis; 69.7% had bicoronal synostosis only, or bicoronal and additional suture synostosis. Three male patients had autism spectrum disorder. Recurrent ear infections were the most common comorbidity, and myringotomy tube placement the most common extracranial surgical procedure. Most patients (76%) required only one fronto-orbital advancement. de novo mutations were confirmed in 33% of the families in which proband and both parents were genetically tested, while in the remaining 66% one of the parents was a mutation carrier. In affected parents, 40% had craniosynostosis, including 71% of mothers and 13% of fathers. We additionally analyzed the medical resource utilization of probands with Muenke syndrome. To our knowledge, these data represent the first comprehensive examination of long-term management in a large cohort of patients with Muenke syndrome. Our study adds valuable information regarding neuropsychiatric and medical comorbidities, and highlights findings in affected relatives.
- Published
- 2019
72. Further delineation of the phenotypic spectrum of nevus comedonicus syndrome to include congenital pulmonary airway malformation of the lung and aneurysm
- Author
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Leslie Castelo-Soccio, Julie S. Moldenhauer, Elizabeth J. Bhoj, Mark Fitzgerald, Katheryn Grand, William H. Peranteau, Jennifer Pogoriler, Erica Schindewolf, Anna Smith, Patrick McMahon, Sarah E Sheppard, Adam I. Rubin, and Pablo Laje
- Subjects
0301 basic medicine ,Male ,Nevus comedonicus ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Nevus comedonicus syndrome ,030105 genetics & heredity ,Article ,03 medical and health sciences ,Aneurysm ,Cystic Adenomatoid Malformation of Lung, Congenital ,Genetics ,medicine ,Humans ,NIMA-Related Kinases ,skin and connective tissue diseases ,Nevus ,Genetics (clinical) ,Lung ,business.industry ,Congenital pulmonary airway malformation ,Infant ,medicine.disease ,Epidermal nevus syndrome ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Scalp ,Mutation ,business ,Pigmentation Disorders - Abstract
Nevus comedonicus syndrome (NCS) is a rare epidermal nevus syndrome characterized by ocular, skeletal, and central nervous system anomalies. We present a 23-month-old boy with a history of a congenital pulmonary airway malformation (CPAM) of the lung and a congenital cataract who developed progressive linear and curvilinear plaques of dilated follicular openings with keratin plugs (comedones) on parts of his scalp, face, and body consistent with nevus comedonicus. MRI of the brain demonstrated an aneurysm of the right internal carotid artery. Genetic testing identified NEK9 c.1755_1757del (p.Thr586del) at mean allele frequency of 28% in the nevus comedonicus. This same mutation was present in the CPAM tissue. This is the first case of a CPAM in a patient with an epidermal nevus syndrome. This case expands the phenotype of nevus comedonicus syndrome to include CPAM and vascular anomalies.
- Published
- 2019
73. Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome
- Author
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Karen W. Gripp, Laurie A. Demmer, Bekim Sadikovic, Jennifer Kerkhof, Eric G. Bend, Heather Davis, R. Curtis Rogers, Paul R. Mark, Michael A. Levy, Elizabeth J. Bhoj, Sara S. Cathey, Dong Li, Hakon Hakonarson, Alan Stuart, Michael J. Friez, Elaine H. Zackai, Erfan Aref-Eshghi, Charles E. Schwartz, Eloise J. Prijoles, Katie Clarkson, Roger E. Stevenson, David I. Rodenhiser, Michael J. Lyons, and David B. Everman
- Subjects
0301 basic medicine ,Male ,Autism Spectrum Disorder ,Autism ,Intellectual disability ,lcsh:Medicine ,Disease screening ,Pediatrics ,Epigenesis, Genetic ,0302 clinical medicine ,Helsmoortel-Van der Aa syndrome ,Global developmental delay ,Episignature ,Child ,Genetics (clinical) ,ADNP ,Genetics ,DNA methylation ,Unresolved clinical cases ,Chromatin ,030220 oncology & carcinogenesis ,Child, Preschool ,Epigenetics ,Female ,lcsh:QH426-470 ,Nerve Tissue Proteins ,Biology ,DNA sequencing ,03 medical and health sciences ,Humans ,Molecular Biology ,Gene ,Homeodomain Proteins ,Models, Genetic ,Research ,lcsh:R ,Computational Biology ,Human genetics ,genomic DNA ,lcsh:Genetics ,030104 developmental biology ,Early Diagnosis ,Neurodevelopmental Disorders ,Mutation ,CpG Islands ,Developmental Biology - Abstract
Background ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methylation patterns that could be used in the molecular diagnosis of ADNP syndrome. Results We identified two distinct and partially opposing genomic DNA methylation episignatures in the peripheral blood samples from 22 patients with ADNP syndrome. The “epi-ADNP-1” episignature included ~ 6000 mostly hypomethylated CpGs, and the “epi-ADNP-2” episignature included ~ 1000 predominantly hypermethylated CpGs. The two signatures correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N- and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. The episignatures were enriched for genes involved in neuronal system development and function. A classifier trained on these profiles yielded full sensitivity and specificity in detecting patients with either of the two episignatures. Applying this model to seven patients with uncertain clinical diagnosis enabled reclassification of genetic variants of uncertain significance and assigned new diagnosis when the primary clinical suspicion was not correct. When applied to a large cohort of unresolved patients with developmental delay (N = 1150), the model predicted three additional previously undiagnosed patients to have ADNP syndrome. DNA sequencing of these subjects, wherever available, identified pathogenic mutations within the gene domains predicted by the model. Conclusions We describe the first Mendelian condition with two distinct episignatures caused by mutations in a single gene. These highly sensitive and specific DNA methylation episignatures enable diagnosis, screening, and genetic variant classifications in ADNP syndrome. Electronic supplementary material The online version of this article (10.1186/s13148-019-0658-5) contains supplementary material, which is available to authorized users.
- Published
- 2019
74. Isolated vocal cord paralysis in two siblings with compound heterozygous variants inMUSK: Expanding the phenotypic spectrum
- Author
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Elizabeth J. Bhoj, Hakon Hakonarson, Dong Li, Katheryn Grand, and Chaya N. Murali
- Subjects
Male ,Heterozygote ,Weakness ,Pathology ,medicine.medical_specialty ,Proximal muscle weakness ,Compound heterozygosity ,Article ,Neuromuscular junction ,Genetics ,medicine ,Humans ,Receptors, Cholinergic ,Vocal cord paralysis ,Child ,Genetics (clinical) ,Exome sequencing ,Acetylcholine receptor ,business.industry ,Siblings ,Infant ,Receptor Protein-Tyrosine Kinases ,Prognosis ,medicine.disease ,Phenotype ,medicine.anatomical_structure ,Mutation ,Speech delay ,medicine.symptom ,business ,Vocal Cord Paralysis - Abstract
The congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by perturbations in signal transduction at the neuromuscular junction. Defects in muscle, skeletal, receptor tyrosine kinase (MuSK) cause two distinct phenotypes: fetal akinesia with multiple congenital anomalies (Fetal akinesia deformation sequence [MIM:208150]) and early onset congenital myasthenia (myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency [MIM:616325]). Myasthenia due to MuSK deficiency has variable clinical features, ranging from a milder presentation of isolated late-onset proximal muscle weakness; to a severe presentation of prenatal-onset diffuse weakness, ophthalmoplegia, respiratory failure, and vocal cord paralysis (VCP). Here, we propose to expand the phenotypic spectrum for MuSK deficiency to include isolated VCP with the absence of other classical myasthenic symptoms. We evaluated two brothers who presented in the neonatal period with respiratory failure secondary to isolated VCP. Research-based exome sequencing revealed biallelic likely pathogenic variants in MUSK (MIM:601296). Both children had normal gross motor and fine motor development. One brother had speech delay, likely due to a combination of tracheostomy status and ankyloglossia. This case report suggests that CMS should be on the differential diagnosis for familial recurrence of VCP.
- Published
- 2019
75. SMARCE1, a rare cause of Coffin-Siris Syndrome: Clinical description of three additional cases
- Author
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Noriko Miyake, Yuri A. Zarate, Afifa Irani, Elizabeth J. Bhoj, Hakon Hakonarson, Naomichi Matsumoto, Shubha R. Phadke, Yoshinori Tsurusaki, Dong Li, Samantha A. Schrier Vergano, Luis F. Escobar, and Julie Kaylor
- Subjects
Male ,0301 basic medicine ,Proband ,Hypertrichosis ,medicine.medical_specialty ,Genotype ,ARID1A ,Chromosomal Proteins, Non-Histone ,Micrognathism ,Article ,03 medical and health sciences ,Intellectual Disability ,otorhinolaryngologic diseases ,Genetics ,Humans ,Medicine ,Abnormalities, Multiple ,Exome ,SMARCB1 ,Child ,Coffin–Siris syndrome ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Exome sequencing ,Coarse facial features ,business.industry ,Facies ,High-Throughput Nucleotide Sequencing ,Infant ,Exons ,medicine.disease ,Dermatology ,DNA-Binding Proteins ,Phenotype ,030104 developmental biology ,Child, Preschool ,Face ,Mutation ,SMARCA4 ,Female ,business ,Hand Deformities, Congenital ,Neck - Abstract
Coffin-Siris syndrome (CSS, MIM 135900), is a well-described, multiple congenital anomaly syndrome characterized by coarse facial features, hypertrichosis, sparse scalp hair, and hypo/aplastic digital nails and phalanges, typically of the 5th digits. Mutations in the BAF (SWI/SNF)-complex subunits (SMARCA4, SMARCE1, SMARCB1, SMARCA2, ARID1B, and ARID1A) have been shown to cause not only CSS, but also related disorders including Nicolaides-Baraitser (MIM 601358) syndrome and ARID1B-intellectual disability syndrome (MIM 614562). At least 200 individuals with CSS have been found to have a mutation in the BAF pathway. However, to date, only three individuals with CSS have been reported to have pathogenic variants in SMARCE1. We report here three additional individuals with clinical features consistent with CSS and alterations in SMARCE1, one of which is novel. The probands all exhibited dysmorphic facial features, moderate developmental and cognitive delay, poor growth, and hypoplastic digital nails/phalanges, including digits not typically affected in the other genes associated with CSS. Two of the three probands had a variety of different organ system anomalies, including cardiac disease, genitourinary abnormalities, feeding difficulties, and vision abnormalities. The 3rd proband has not had further investigative studies. Although an increasing number of individuals are being diagnosed with disorders in the BAF pathway, SMARCE1 is the least common of these genes. This report doubles the number of probands with these mutations, and allows for better phenotypic information of this rare syndrome. © 2016 Wiley Periodicals, Inc.
- Published
- 2016
76. Imprinted genes in clinical exome sequencing: Review of 538 cases and exploration of mouse-human conservation in the identification of novel human disease loci
- Author
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Avni Santani, Samuel W. Baker, Elizabeth J. Bhoj, Farrah Rajabi, and Wen-Hann Tan
- Subjects
0301 basic medicine ,medicine.medical_specialty ,030105 genetics & heredity ,Biology ,Genomic Imprinting ,Mice ,03 medical and health sciences ,Databases, Genetic ,Genetics ,medicine ,Animals ,Humans ,Exome ,Imprinting (psychology) ,Conserved Sequence ,Genetics (clinical) ,Exome sequencing ,Whole Genome Sequencing ,Genetic Diseases, Inborn ,General Medicine ,medicine.disease ,Molecular diagnostics ,Uniparental disomy ,030104 developmental biology ,Genetic Loci ,Mutation ,DIRAS3 ,Medical genetics ,Human genome ,Genomic imprinting - Abstract
Human imprinting disorders cause a range of dysmorphic and neurocognitive phenotypes, and they may elude traditional molecular diagnosis such exome sequencing. The discovery of novel disorders related to imprinted genes has lagged behind traditional Mendelian disorders because current diagnostic technology, especially unbiased testing, has limited utility in their discovery. To identify novel imprinting disorders, we reviewed data for every human gene hypothesized to be imprinted, identified each mouse ortholog, determined its imprinting status in the mouse, and analyzed its function in humans and mice. We identified 17 human genes that are imprinted in both humans and mice, and have functional data in mice or humans to suggest that dysregulated expression would lead to an abnormal phenotype in humans. These 17 genes, along with known imprinted genes, were preferentially flagged 538 clinical exome sequencing tests. The identified genes were: DIRAS3 [1p31.3], TP73 [1p36.32], SLC22A3 [6q25.3], GRB10 [7p12.1], DDC [7p12.2], MAGI2 [7q21.11], PEG10 [7q21.3], PPP1R9A [7q21.3], CALCR [7q21.3], DLGAP2 [8p23.3], GLIS3 [9p24.2], INPP5F [10q26.11], ANO1 [11q13.3], SLC38A4 [12q13.11], GATM [15q21.1], PEG3 [19q13.43], and NLRP2 [19q13.42]. In the 538 clinical cases, eight cases (1.7%) reported variants in a causative known imprinted gene. There were 367/758 variants (48.4%) in imprinted genes that were not known to cause disease, but none of those variants met the criteria for clinical reporting. Imprinted disorders play a significant role in human disease, and additional human imprinted disorders remain to be discovered. Therefore, evolutionary conservation is a potential tool to identify novel genes involved in human imprinting disorders and to identify them in clinical testing.
- Published
- 2020
77. Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes
- Author
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Dominique Bonneau, Luis A Gonzalez-Nieto, Stine Leenskjold, Patrick Callier, Isabelle Thiffault, Katheryn Grand, Pauline Bogaard, Séverine Drunat, Elizabeth J. Bhoj, Hakon Hakonarson, Katherine T. Wild, Elaine H. Zackai, Elena Repnikova, Damien Haye, Irene K Nielsen, Mirena C Astiazaran, Irfan Saadi, Daphné Lehalle, Ida Charlotte Bay Lund, Shivarajan M. Amudhavalli, Annick Toutain, Alain Verloes, Ana Sofia Carvalho, Dong Li, Carol J Saunders, Yoann Vial, Kadri Karaer, The Center for Applied Genomics [Philadelphia, PA, USA], Children’s Hospital of Philadelphia (CHOP ), Division of Human Genetics [Philadelphia, PA, USA], Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Coimbra [Portugal] (UC), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Oak Ridge National Laboratory [Oak Ridge] (ORNL), UT-Battelle, LLC, The Center for Applied Genomics, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
0301 basic medicine ,Nosology ,Male ,Opitz BBBG syndrome ,[SDV]Life Sciences [q-bio] ,030105 genetics & heredity ,Craniofacial Abnormalities ,Cranial neural crest ,Intellectual disability ,SPECC1L ,Child ,Genetics (clinical) ,Growth Disorders ,Genetics ,Hypospadias ,Hypertelorism ,General Medicine ,Omphalocele ,Pedigree ,Phenotype ,Child, Preschool ,Female ,Hand Deformities, Congenital ,Hydrocephalus ,Adult ,Adolescent ,Foot Deformities, Congenital ,Biology ,Actin cytoskeleton organization ,Article ,Craniosynostosis ,03 medical and health sciences ,Esophagus ,medicine ,Teebi hypertelorism syndrome ,Humans ,Abnormalities, Multiple ,Obesity ,Craniofacial ,Bicornuate uterus ,MID1 ,Facies ,medicine.disease ,Phosphoproteins ,030104 developmental biology ,Mutation ,Mental Retardation, X-Linked ,Spindle organization - Abstract
International audience; The SPECC1L protein plays a role in adherens junctions involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. It modulates PI3K-AKT signaling and controls cranial neural crest cell delamination during facial morphogenesis. SPECC1L causative variants were first identified in individuals with oblique facial clefts. Recently, causative variants in SPECC1L were reported in a pedigree reported in 1988 as atypical Opitz GBBB syndrome. Six families with SPECC1L variants have been reported thus far. We report here eight further pedigrees with SPECC1L variants, including a three-generation family, and a further individual of a previously published family. We discuss the nosology of Teebi and GBBB, and the syndromes related to SPECC1L variants. Although the phenotype of individuals with SPECC1L mutations shows overlap with Opitz syndrome in its craniofacial anomalies, the canonical laryngeal malformations and male genital anomalies are not observed. Instead, individuals with SPECCL1 variants have branchial fistulae, omphalocele, diaphragmatic hernias, and uterus didelphis. We also point to the clinical overlap of SPECC1L syndrome with mild Baraitser-Winter craniofrontofacial syndrome: they share similar dysmorphic features (wide, short nose with a large tip, cleft lip and palate, blepharoptosis, retrognathia, and craniosynostosis), although intellectual disability, neuronal migration defect, and muscular problems remain largely specific to Baraitser-Winter syndrome. In conclusion, we suggest that patients with pathogenic variants in SPECC1L should not be described as "dominant (or type 2) Opitz GBBB syndrome", and instead should be referred to as "SPECC1L syndrome" as both disorders show distinctive, non overlapping developmental anomalies beyond facial communalities.
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- 2018
78. Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly
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Patrick M. A. Sleiman, Marina Bakay, Lifeng Tian, Charlly Kao, Tara L. Wenger, Nora Robinson, Yoav Dori, Alvaro Gutierrez-Uzquiza, Renata Pellegrino da Silva, Cuiping Hou, Maxim Itkin, Patricia J. Hicks, Mechenzie Behr, Dong Li, Tiancheng Wang, Misha Rosenbach, Yichuan Liu, Rosetta M. Chiavacci, Michael E. March, Christoph Seiler, Michael A. Levine, Jonathan A. Perkins, Elizabeth J. Bhoj, and Hakon Hakonarson
- Subjects
0301 basic medicine ,Heterozygote ,Morpholino ,Mutant ,Receptor, EphB4 ,Biology ,Mechanistic Target of Rapamycin Complex 1 ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Exome Sequencing ,Genetics ,medicine ,Lymphatic vessel ,Animals ,Humans ,Phosphorylation ,Molecular Biology ,Zebrafish ,Genetics (clinical) ,Lymphatic Vessels ,Mutation ,Lymphatic Abnormalities ,HEK 293 cells ,Receptor Protein-Tyrosine Kinases ,General Medicine ,Transfection ,biology.organism_classification ,Molecular biology ,Pedigree ,Disease Models, Animal ,030104 developmental biology ,Lymphatic system ,medicine.anatomical_structure ,HEK293 Cells ,030220 oncology & carcinogenesis ,Original Article ,Signal Transduction - Abstract
Central conducting lymphatic anomaly (CCLA) is one of the complex lymphatic anomalies characterized by dilated lymphatic channels, lymphatic channel dysmotility and distal obstruction affecting lymphatic drainage. We performed whole exome sequencing (WES) of DNA from a four-generation pedigree and examined the consequences of the variant by transfection of mammalian cells and morpholino and rescue studies in zebrafish. WES revealed a heterozygous mutation in EPHB4 (RefSeq NM_004444.4; c.2334 + 1G>C) and RNA-Seq demonstrated that the EPHB4 mutation destroys the normal donor site, which leads to the use of a cryptic splice donor that results in retention of the intervening 12-bp intron sequence. Transient co-expression of the wild-type and mutant EPHB4 proteins showed reduced phosphorylation of tyrosine, consistent with a loss-of-function effect. Zebrafish ephb4a morpholino resulted in vessel misbranching and deformities in the lymphatic vessel development, indicative of possible differentiation defects in lymphatic vessels, mimicking the lymphatic presentations of the patients. Immunoblot analysis using zebrafish lysates demonstrated over-activation of mTORC1 as a consequence of reduced EPHB4 signaling. Strikingly, drugs that inhibit mTOR signaling or RAS-MAPK signaling effectively rescued the misbranching phenotype in a comparable manner. Moreover, knock-in of EPHB4 mutation in HEK293T cells also induced mTORC1 activity. Our data demonstrate the pathogenicity of the identified EPHB4 mutation as a novel cause of CCLA and suggesting that ERK inhibitors may have therapeutic benefits in such patients with complex lymphatic anomalies.
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- 2018
79. Extension of the mutational and clinical spectrum of SOX2 related disorders: Description of six new cases and a novel association with suprasellar teratoma
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Sofia Perez-Solorzano, Iris G. Tirado-Torres, Xilma R. Ortiz-Gonzalez, Jessica Nava, Pavel N. Pichurin, Joseph E. Parisi, Juan Carlos Zenteno, Patrick R. Blackburn, Rachael A. Vaubel, Shabnam Zarei, Oscar F. Chacon-Camacho, Cristina Villanueva-Mendoza, Mariana Reyes, Graciela Areli López-Uriarte, Vianney Cortés-González, Dong Li, Eric W. Klee, Marine I. Murphree, and Elizabeth J. Bhoj
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0301 basic medicine ,Male ,Biopsy ,Context (language use) ,030105 genetics & heredity ,Bioinformatics ,Microphthalmia ,03 medical and health sciences ,Consanguinity ,Imaging, Three-Dimensional ,SOX2 ,Intellectual disability ,Exome Sequencing ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Eye Abnormalities ,Genetics (clinical) ,Genetic Association Studies ,Anophthalmia ,business.industry ,SOXB1 Transcription Factors ,Skull ,Infant, Newborn ,Teratoma ,Brain ,Facies ,Infant ,Sequence Analysis, DNA ,medicine.disease ,Magnetic Resonance Imaging ,030104 developmental biology ,Phenotype ,Atresia ,Child, Preschool ,embryonic structures ,Mutation ,Autism ,Female ,sense organs ,business ,Tomography, X-Ray Computed - Abstract
SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss-of-function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation-positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow-growing hypothalamo-pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation.
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- 2018
80. ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor
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Dong, Li, Michael E, March, Alvaro, Gutierrez-Uzquiza, Charlly, Kao, Christoph, Seiler, Erin, Pinto, Leticia S, Matsuoka, Mark R, Battig, Elizabeth J, Bhoj, Tara L, Wenger, Lifeng, Tian, Nora, Robinson, Tiancheng, Wang, Yichuan, Liu, Brant M, Weinstein, Matthew, Swift, Hyun Min, Jung, Courtney N, Kaminski, Rosetta, Chiavacci, Jonathan A, Perkins, Michael A, Levine, Patrick M A, Sleiman, Patricia J, Hicks, Janet T, Strausbaugh, Jean B, Belasco, Yoav, Dori, and Hakon, Hakonarson
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Adult ,Male ,Mitogen-Activated Protein Kinase Kinases ,Lymphatic Abnormalities ,Pyridones ,Pyrimidinones ,Proto-Oncogene Proteins A-raf ,HEK293 Cells ,Mutation ,Exome Sequencing ,Animals ,Humans ,Female ,Child ,Zebrafish - Abstract
The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations
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- 2018
81. MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype
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Bertrand Isidor, Christine Francannet, D. Li, Samuel W. Baker, Gaëlle Vieville, Martine Doco-Fenzy, David Geneviève, I. Giurgea, Anna Gréen, Emily Fassi, Caroline Nava, Roseline Caumes, C. Fournier, Alexandra Afenjar, Françoise Devillard, Yuri A. Zarate, Damien Sanlaville, Michael Field, Elisabetta Lapi, Sandra Whalen, Emma Bedoukian, Alice Goldenberg, S. Steinwall Larsen, Jamal Ghoumid, Marjolaine Willems, M. Wenzel, Isabelle Marey, Sylvie Picker-Minh, Thomas Smol, Anne-Marie Guerrot, Dominique Bonneau, Gaetan Lesca, Delphine Héron, Elizabeth J. Bhoj, Véronique Satre, Sylvie Manouvrier-Hanu, Christine Coubes, Alain Verloes, Margarita Stefanova, Gaël Nicolas, Amélie Piton, Odile Boute-Benejean, Laurence Faivre, Caroline Thuillier, Bénédicte Gérard, Nicolas Chatron, Florence Petit, Beth Keena, Elise Boudry-Labis, C. Colson, Sonia Bouquillon, Avni Santani, Boris Keren, Lisa Ewans, Tony Roscioli, N. Le Meur, Paul Kuentz, Bryan L. Krock, Catherine Roche-Lestienne, Anne Dieux-Coeslier, Alban Ziegler, Pascale Saugier-Veber, Cyril Mignot, Vera M. Kalscheuer, Addie I. Nesbitt, Charles Coutton, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), CHU Trousseau [APHP], Children’s Hospital of Philadelphia (CHOP ), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de Génétique Chromosomique [CHU de Grenoble], CHU Grenoble, University of New South Wales [Canberra Campus] (UNSW), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Linköping university hospital, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Azienda Ospedaliero Universitaria A. Meyer [Firenze, Italy], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, University of Arkansas for Medical Sciences (UAMS), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de génétique et embryologie médicales [CHU Trousseau], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Montpellier, Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction ( RADEME ), Hôpital Jeanne de Flandre [Lille]-Université de Lille-Centre Hospitalier Régional Universitaire de Lille ( CHRU de Lille ) -Clinique de Génétique médicale Guy Fontaine [CHRU LIlle]-Centre de référence maladies rares Anomalies du développement [CHRU Lille], Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire de Probabilités et Modèles Aléatoires (LPMA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de Génétique Clinique, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, Laboratoire Hippolyte Fizeau (FIZEAU), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Systèmes de Référence Temps Espace (SYRTE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), APERAM, Inconnu, CHU Clermont-Ferrand, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), FHU TRANSLAD, Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Pitié-Salpêtrière [APHP], Fossil Fuel Chemistry, University of Sofia, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and International Livestock Research Institute
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Pediatrics ,Ataxia ,Mutation, Missense ,Intellectual disability ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,MESH: Phenotype ,MESH: Intellectual Disability ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Epilepsy ,MESH: Mediator Complex ,MESH: Child ,Genetics ,medicine ,Missense mutation ,Humans ,Mediator complex ,Child ,[ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics ,Genetics (clinical) ,MESH: Mutation, Missense ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,MESH: Humans ,business.industry ,MESH: Child, Preschool ,medicine.disease ,Human genetics ,Hypotonia ,MESH: Male ,3. Good health ,MED13L ,Cardiopathy ,030104 developmental biology ,Phenotype ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Child, Preschool ,Medical genetics ,Female ,medicine.symptom ,Haploinsufficiency ,business ,MESH: Female ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
IF 3.269; International audience; Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.
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- 2018
82. De novo variants in Myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies
- Author
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Hailey Pinz, Jennifer Tarpinian, Elaine H. Zackai, Kristin G. Monaghan, Dong Li, Elizabeth J. Bhoj, Kosuke Izumi, Louise C. Pyle, Cara M. Skraban, Aida Telegrafi, and Stephen R. Braddock
- Subjects
Heart Defects, Congenital ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Genotype ,Article ,03 medical and health sciences ,Pulmonary hypoplasia ,0302 clinical medicine ,Gene Frequency ,Scimitar syndrome ,Genetics ,Medicine ,Humans ,Genetic Predisposition to Disease ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Exome sequencing ,Thymic involution ,Lung ,business.industry ,Thyroid ,Myelin regulatory factor ,Genetic Variation ,Membrane Proteins ,Congenital diaphragmatic hernia ,Syndrome ,medicine.disease ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Child, Preschool ,Urogenital Abnormalities ,Mutation ,business ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated with the control of the expression of myelin-related genes. However, it is highly expressed in human tissues and mouse embryonic tissues outside the nervous system such as the stomach, lung, and small intestine. It has not previously been reported as a cause of any Mendelian disease. We report here two males with Scimitar syndrome [MIM 106700], and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis. Gross neurologic functioning appears to be within normal limits. In both individuals a de novo variant in MYRF was identified using exome sequencing. Neither variant is found in gnomAD. Heterozygous variants in MYRF should be considered in patients with variants of Scimitar syndrome and urogenital anomalies.
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- 2018
83. Embryology and Anatomy of the Developing Face
- Author
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Bart P. Leroy, Elizabeth J. Bhoj, and Lama Khatib
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business.industry ,Embryology ,fungi ,food and beverages ,Medicine ,sense organs ,Anatomy ,Craniofacial ,Neural crest cell migration ,business - Abstract
The study of embryology and human morphology can provide an enhanced understanding of anatomy in surgical intervention. This chapter will review the critical stages in embryologic development of the human face and how alterations in normal development can produce syndromic and non-syndromic changes in craniofacial, adnexal, and orbital structures.
- Published
- 2017
84. Aortic coarctation and carotid artery aneurysm in a patient with hardikar syndrome: Cardiovascular implications for affected individuals
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Elizabeth J. Bhoj, Samantha A. Schrier Vergano, Kaitlin M. Ryan, Hakon Hakonarson, Reem H. Raafat, Alexander R. Ellis, and Dong Li
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Carotid Artery Diseases ,0301 basic medicine ,medicine.medical_specialty ,Heart disease ,medicine.medical_treatment ,Coarctation of the aorta ,Liver transplantation ,Aortic Coarctation ,03 medical and health sciences ,Aneurysm ,Cholestasis ,Internal medicine ,Angioplasty ,Genetics ,medicine ,Humans ,Genetics (clinical) ,business.industry ,Infant, Newborn ,Prognosis ,medicine.disease ,Cleft Palate ,Transplantation ,030104 developmental biology ,Etiology ,Cardiology ,Female ,business ,Retinitis Pigmentosa - Abstract
Hardikar syndrome is a multiple congenital anomaly syndrome first characterized in 1992 by Hardikar et al. to describe two individuals with cholestasis, cleft lip/palate, retinal pigmentation, intestinal abnormalities, and genitourinary anomalies. Between 1992 and 2002, four individuals with Hardikar syndrome were reported in the literature. The fourth individual [Maluf et al. (2002), Transplantation 74:1058-1061; Poley and Proud (2008) Am J Med Genet Part A 146A:2473-2479], who had progressive cholestatic liver disease ultimately requiring liver transplantation, has continued to be followed at our institution. Recently, at the age of 14 years, during an evaluation for refractory hypertension, she was found to have developed coarctation of the aorta that was treated with aortic angioplasty and stenting, dramatically improving her hypertension. Further vascular investigation also revealed a small aneurysm of her carotid artery requiring neurosurgical evaluation and anticoagulant therapy. To our knowledge, these vascular anomalies have not been reported in Hardikar syndrome and the high association of congenital heart disease in the individuals with Hardikar syndrome has not been further addressed. Herein, we discuss this additional clinical information, speculate briefly on possible molecular etiologies, and discuss potential cardiac surveillance recommendations. We hope that broadening the known phenotype of this very rare disorder will further aid clinicians in their management and surveillance for these individuals.
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- 2015
85. Exome sequencing expands the mechanism of SOX5-associated intellectual disability: A case presentation with review of sox-related disorders
- Author
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Mahdi Sarmady, Holly Dubbs, Tanya Tischler, Elaine H. Zackai, Kajia Cao, Kristin McDonald Gibson, Elizabeth J. Bhoj, Addie I. Nesbitt, Zhenming Yu, Avni Santani, and Elizabeth Denenberg
- Subjects
Adult ,Proband ,Adolescent ,Molecular Sequence Data ,Biology ,Bioinformatics ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Humans ,Exome ,Global developmental delay ,Genetics (clinical) ,Loss function ,Exome sequencing ,Base Sequence ,Genetic heterogeneity ,Exons ,Sequence Analysis, DNA ,medicine.disease ,Codon, Nonsense ,Female ,Haploinsufficiency ,SOXD Transcription Factors ,SOX gene family - Abstract
The SOX5 haploinsufficiency syndrome is characterized by global developmental delay, intellectual disability, language and motor impairment, and distinct facial features. The smallest deletion encompassed only one gene, SOX5 (OMIM 604975), indicating that haploinsufficiency of SOX5 contributes to neuro developmental delay. Although multiple deletions of the SOX5 gene have been reported in patients, none are strictly intragenic point mutations. Here, we report the identification of a de novo loss of function variant in SOX5 identified through whole exome sequencing. The proband presented with moderate developmental delay, bilateral optic atrophy, mildly dysmorphic features, and scoliosis, which correlates with the previously-described SOX5-associated phenotype. These results broaden the diagnostic spectrum of SOX5-related intellectual disability. Furthermore it highlights the utility of exome sequencing in establishing an etiological basis in clinically and genetically heterogeneous conditions such as intellectual disability. © 2015 Wiley Periodicals, Inc.
- Published
- 2015
86. Beare-Stevenson syndrome: Two new patients, including a novel finding of tracheal cartilaginous sleeve
- Author
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Elizabeth J. Bhoj, Thomas J. Mollen, Scott P. Bartlett, Elaine H. Zackai, Ralph F. Wetmore, Donna M. McDonald-McGinn, Michael T. Mennuti, and Tara L. Wenger
- Subjects
musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,Pediatrics ,medicine.medical_specialty ,Genetic counseling ,DNA Mutational Analysis ,Mutation, Missense ,Autopsy ,Prenatal diagnosis ,Sudden death ,Ultrasonography, Prenatal ,Craniosynostosis ,Craniosynostoses ,Fatal Outcome ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Acanthosis Nigricans ,Beare–Stevenson cutis gyrata syndrome ,Receptor, Fibroblast Growth Factor, Type 2 ,Genetics (clinical) ,business.industry ,Infant, Newborn ,Infant ,Crouzon syndrome ,Ear ,Anatomy ,medicine.disease ,Trachea ,Airway Compromise ,Scalp Dermatoses ,Skin Abnormalities ,Female ,sense organs ,business - Abstract
Beare–Stevenson syndrome (BSS) is a rare FGFR2-associated craniosynostosis syndrome with a higher rate of sudden unexplained death than related conditions such as Apert, Pfeiffer, and Crouzon syndromes. BSS presents with craniosynostosis, cutis gyrata, and significant developmental delay in most patients who survive infancy. There have only been 21 reported patients with BSS, which limits prognostication for clinicians and likely does not capture the full extent of the phenotype. Here we report on two additional patients with molecularly confirmed BSS, one each with p.Ser372Tyr and p.Tyr375Cys mutations in FGFR2. Cloverleaf skull was identified prenatally in one patient, with initial concern for Crouzon syndrome. Prenatal 3D ultrasound was performed, but cutis gyrata was only visible on retrospective examination following the clinical diagnosis of BSS after birth. Due to phenotypic overlap with Crouzon syndrome, but worse prognosis, we recommend consideration of prenatal 3D ultrasound and mutation testing for patients with suspected Crouzon to allow for prenatal diagnosis of BSS and to enable appropriate genetic counseling and postnatal care. One of our patients was noted to have a tracheal cartilaginous sleeve, which if present could explain sudden death. Of note, tracheal cartilaginous sleeves have been reported in other FGFR2-related craniosynostosis syndromes, and are associated with 90% risk of death by two years of age without tracheostomy. Tracheal cartilaginous sleeves are often only found incidentally at autopsy as they are difficult to diagnose without direct visualization of the trachea. This association and our experience suggests that BSS patients be evaluated for tracheal cartilaginous sleeve to prevent airway compromise. © 2015 Wiley Periodicals, Inc.
- Published
- 2015
87. Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions
- Author
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Bryn Jones, Stephan Waldmueller, Elizabeth J. Bhoj, Erik G. Puffenberger, Hakon Hakonarson, Nanditha Das, Tiong Yang Tan, Claudia Gonzaga-Jauregui, Ioanna Skubas, Sarah J. Hatsell, Susannah Brydges, Stefanie Eggers, Karlla W. Brigatti, Kevin A. Strauss, Melissa G. Dominguez, Ron A. Deckelbaum, Angelika Riess, Gwenaël Le Guyader, Peter G. Farlie, Virginia Hughes, Peter J Simm, Tobias B. Haack, LiQin Xie, Katharina Steindl, Pascal Joset, Aris N. Economides, Dong Li, Fanny Pelluard, Michael Hofbeck, Chia-Jen Siao, Naomi L. Baker, John D. Overton, Anita Rauch, Valerie Mayne, and Marc Sturm
- Subjects
0301 basic medicine ,Heart Defects, Congenital ,Male ,animal structures ,Craniofacial abnormality ,Developmental Disabilities ,Chromosomes, Human, Pair 20 ,Dwarfism ,Bone Morphogenetic Protein 2 ,Haploinsufficiency ,Biology ,Short stature ,Bone and Bones ,Frameshift mutation ,Craniofacial Abnormalities ,03 medical and health sciences ,Mice ,Transforming Growth Factor beta ,Report ,Genetics ,medicine ,Animals ,Humans ,Craniofacial ,Child ,Genetics (clinical) ,Mice, Knockout ,Infant ,Heart ,medicine.disease ,Phenotype ,Cleft Palate ,Disease Models, Animal ,030104 developmental biology ,Child, Preschool ,Chromosomal region ,embryonic structures ,Female ,medicine.symptom - Abstract
Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.
- Published
- 2017
88. Genetic Considerations in Oculoplastic Disorders
- Author
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Lama Khatib, Bart P. Leroy, Elizabeth J. Bhoj, and Emma Bedoukian
- Subjects
Cognitive science ,medicine.diagnostic_test ,media_common.quotation_subject ,Inheritance (genetic algorithm) ,Context (language use) ,Penetrance ,Punnett square ,Presentation ,Reading (process) ,medicine ,Psychology ,Genetic testing ,media_common ,Test ordering - Abstract
In this chapter we describe some basic genetic principles in the context of oculoplastic disease. We will review genetics starting from chromosome to protein. We will review the interaction between genes and environment and their involvement together in disease or presentation. We will discuss the relationship between gene and phenotype. We will discuss that not all genetic disorders penetrate each generation, a phenomenon called incomplete penetrance. We will discuss how the same condition in a single family can present with a range of symptoms, a lesson called variable expressivity. We will also review the basic anatomy of the human genome. The bulk of the chapter will then focus on recognizable patterns of inheritance. There are illustrations for quick reference to demonstrate each inheritance type. Each illustration includes a diagram including male and female figurines as well as the more classic Punnett squares. These illustrations will help those unfamiliar with genetics grasp the concepts without detailed reading or further exploration. We also review the different types of genetic testing which are chromosomal- and sequence-based tests. We hope these guidelines will allow appropriate test ordering by the oculoplastic physician.
- Published
- 2017
89. Expanding the phenotypic spectrum of TP63-related disorders including the first set of monozygotic twins
- Author
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Wen-Hann Tan, Zornitza Stark, Elizabeth J. Bhoj, Margaret Harr, Hakon Hakonarson, Renata Pellegrino, Dong Li, and Tara L. Wenger
- Subjects
0301 basic medicine ,Adult ,Male ,Ectodermal dysplasia ,medicine.medical_specialty ,Ectrodactyly ,Adolescent ,Genotype ,Choanal atresia ,030105 genetics & heredity ,03 medical and health sciences ,Young Adult ,TP63 ,Hydrocele ,Genetics ,medicine ,Humans ,Child ,Genetics (clinical) ,Alleles ,Genetic Association Studies ,Newborn screening ,Severe combined immunodeficiency ,business.industry ,Tumor Suppressor Proteins ,Facies ,Anatomy ,Twins, Monozygotic ,medicine.disease ,Dermatology ,Pedigree ,medicine.anatomical_structure ,Phenotype ,Amino Acid Substitution ,Child, Preschool ,Mutation ,Nail (anatomy) ,Female ,business ,Transcription Factors - Abstract
Individuals with Tumor Protein P63 (TP63)-related disorders are known to present with a range of phenotypic features, including ectrodactyly, ectodermal dysplasia, cleft lip/palate, Rapp-Hodgkin, Hay-Wells, and limb-mammary syndromes. We present six individuals from three families, including a set of monozygotic twins, with pathogenic TP63 variants who had novel clinical findings. The twins were discordant for cleft lip and palate, and the type of hand malformations, but concordant for choanal atresia, and bilateral volar nail. Both failed newborn screening for severe combined immunodeficiency (SCID) due to T-cell lymphopenia. The second family included three family members across two generations. Two of these three family members had orofacial clefting, but the remaining child had a laryngeal web and hydrocele with no clefting or hand anomalies, highlighting the variable expressivity in TP63-related disorders. The individual from the third family had unilateral cleft lip and palate, hydronephrosis, and bilateral volar nails. Together, these cases illustrate that: there is significant familial variability, including discordant major but concordant minor anomalies in the first ever reported set of molecularly confirmed monozygotic twins with pathogenic variants in TP63; pathogenic variants in TP63 should be considered in individuals with volar nail, which was previously only strongly associated with 4q34 deletion syndrome; and failed SCID newborn screening due to abnormal immune functioning may be part of the phenotypic spectrum of TP63-related disorders, as it was reported in one prior individual and two of the individuals in our case series.
- Published
- 2017
90. 3548 De novo germline variants in Histone 3 Family 3A (H3F3A) and Histone 3 Family 3B (H3F3B) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations
- Author
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Elizabeth J. Bhoj and Divya Nair
- Subjects
Genetics ,Mechanistic Basic to Clinical ,H3F3B ,Histone ,Germline mutation ,biology ,Somatic cell ,DNA repair ,biology.protein ,General Medicine ,Epigenetics ,Germline ,Chromatin - Abstract
OBJECTIVES/SPECIFIC AIMS: Histones are nuclear proteins that associate with DNA to facilitate packaging into condensed chromatin. Histones are dynamically decorated with post-translational modifications (PTMs), which regulate such processes as DNA repair, gene expression, mitosis, and meiosis. Histone 3 Family 3 (H3F3) histones (H3.3), encoded by H3F3A and H3F3B, mark active genes, maintain epigenetic memory, and maintain heterochromatin and telomeric integrity. Specific somatic mutations in H3F3A and H3F3B have been strongly associated with pediatric glia and other tumors, but no germline mutations have been reported. The goal of our study was to further understand the functional effects of germline mutations of H3F3A and H3F3B. METHODS/STUDY POPULATION: We analyzed 32 patients bearing de novo germline missense mutations in H3F3A or H3F3B with core phenotypes of progressive neurologic dysfunction and congenital anomalies, but no malignancies. Patient histones were analyzed by quantitative mass spectrometry (qMS). RESULTS/ANTICIPATED RESULTS: qMS results revealed that the mutant histone proteins are present at a concentration similar to that of wild-type H3.3. qMS analysis showed strikingly aberrant PTM patterns that suggested local dysregulation. These patterns are distinct from the dominant negative somatic mutations, which cause more global PTM dysregulation. Patient cells also demonstrated upregulation of the expression of genes related to mitosis and cell division, and had a greater proliferative capacity. DISCUSSION/SIGNIFICANCE OF IMPACT: Our data suggests that the pathogenic mechanism of germline histone mutations is distinct from that of the published cancer-associated somatic histone mutations, but may converge on control of cell proliferation. Further clarification of the pathophysiology in these patients can elucidate the roles of histones and histone PTMs in human development and non-syndromic neurodegeneration. In addition, it provides a framework for targeted therapy development for this and related progressive neurologic disorders.
- Published
- 2019
91. Expanding the spectrum of microdeletion 4q21 syndrome: A partial phenotype with incomplete deletion of the minimal critical region and a new association with cleft palate and pierre robin sequence
- Author
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Sara Halbach, Rachel Lande, Elizabeth J. Bhoj, Darrel Waggoner, Elaine H. Zackai, Donna M. McDonald-McGinn, and Christopher A. Tan
- Subjects
Male ,Candidate gene ,Microarray ,Single-nucleotide polymorphism ,Biology ,Genetics ,medicine ,Humans ,SNP ,Hypertelorism ,Child ,Gene ,Genetics (clinical) ,Pierre Robin Syndrome ,Chromosome Mapping ,Facies ,Syndrome ,Phenotype ,Cleft Palate ,Neonatal hypotonia ,Child, Preschool ,Female ,Chromosome Deletion ,Chromosomes, Human, Pair 4 ,medicine.symptom - Abstract
Microdeletion 4q21 syndrome has been described in about a dozen patients with deletions ranging from 3.2 to 15.1 MB with similar features including the distinctive facial characteristics of broad forehead, hypertelorism, and prominent front teeth, with severe growth delay, developmental delay, and neonatal hypotonia. A 1.37 MB minimal critical region has been described that accounts for this shared phenotype and includes five known genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1. We report on two new patients found through single nucleotide polymorphism (SNP) microarray testing that expand the reported phenotype. Patient 1 has a novel deletion of 2.0 MB, the smallest reported deletion, which involves only a partial deletion of the minimal critical region, including the genes HNRNPD, HNRPDL, and ENOPH1. She shares much of the typical phenotype including moderate developmental delay, unusual facial features, small hands and feet, but not any growth delay or neonatal hypotonia. This patient allows further genotype-phenotype correlation of the genes in the minimal critical region, and supports that heterozygous loss of PRKG2 leads to the growth delay. Patient 2 has a novel 3.4 MB deletion that includes the entire critical region, and has typical features, but also presented with cleft palate and Pierre Robin sequence, which have not been previously described. A gene reported to be associated with inherited cleft palate, SCD5, is in the deleted region in this patient, which suggests it may be playing a role in palate formation. Taken together, these patients allow for an expansion of the microdeletion 4q21 syndrome and provide candidate genes for particular features of the phenotype.
- Published
- 2013
92. Tracheal cartilaginous sleeves in children with syndromic craniosynostosis
- Author
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Donna M. McDonald-McGinn, Carrie L. Heike, Elaine H. Zackai, John P. Dahl, Kathleen C.Y. Sie, Anna Rosén, Anne Hing, Elizabeth J. Bhoj, Tara L. Wenger, Ian N. Jacobs, Michael L. Cunningham, Avni Santani, Jonathan A. Perkins, and Andrew F. Inglis
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Adolescent ,Genotype ,030105 genetics & heredity ,Sudden death ,Article ,03 medical and health sciences ,Craniosynostoses ,medicine ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Abnormalities, Multiple ,Genetic Testing ,Receptor, Fibroblast Growth Factor, Type 2 ,Child ,Genetics (clinical) ,Genetic testing ,medicine.diagnostic_test ,business.industry ,fungi ,Twist-Related Protein 1 ,Crouzon syndrome ,Nuclear Proteins ,medicine.disease ,Trachea ,030104 developmental biology ,Cartilage ,Otorhinolaryngology ,Child, Preschool ,Cohort ,Mutation ,Pfeiffer syndrome ,Female ,Saethre–Chotzen syndrome ,Airway ,business - Abstract
Because a tracheal cartilaginous sleeve (TCS) confers a significant mortality risk that can be mitigated with appropriate intervention, we sought to describe the prevalence and associated genotypes in a large cohort of children with syndromic craniosynostosis. Chart review of patients with syndromic craniosynostosis across two institutions. In a cohort of 86 patients with syndromic craniosynostosis, 31 required airway evaluation under anesthesia. TCS was found in 19, for an overall prevalence of 22%. FGFR2, TWIST1, and FGFR3 mutations were identified in children with TCS. All five children with a W290C mutation in FGFR2 had TCS, and most previously reported children with W290C had identification of TCS or early death. In contrast, TCS was not associated with other mutations at residue 290. There is an association between TCS and syndromic craniosynostosis, and it appears to be particularly high in individuals with the W290C mutation in FGFR2. Referral to a pediatric otolaryngologist and consideration of operative airway evaluation (i.e., bronchoscopy or rigid endoscopy) in all patients with syndromic craniosynostosis should be considered to evaluate for TCS. Results from genetic testing may help providers weigh the risks and benefits of early airway evaluation and intervention in children with higher-risk genotypes. Genet Med 19 1, 62–68.
- Published
- 2016
93. Early Infantile Epileptic Encephalopathy in an STXBP1 Patient with Lactic Acidemia and Normal Mitochondrial Respiratory Chain Function
- Author
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Tiancheng Wang, Fengxiang Wang, Elizabeth M. McCormick, Dong Li, Yan Zhao, Lifeng Tian, Marni J. Falk, Cecilia Kim, Rosetta M. Chiavacci, Elizabeth J. Bhoj, Hakon Hakonarson, and James Snyder
- Subjects
0301 basic medicine ,Proband ,Episodic ataxia ,Pathology ,medicine.medical_specialty ,Movement disorders ,lcsh:QH426-470 ,business.industry ,Mitochondrial disease ,Case Report ,General Medicine ,medicine.disease ,Syntaxin binding ,03 medical and health sciences ,Epilepsy ,lcsh:Genetics ,030104 developmental biology ,0302 clinical medicine ,Mitochondrial respiratory chain ,STXBP1 ,Medicine ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
A wide range of clinical findings have been associated with mutations in Syntaxin Binding Protein 1 (STXBP1), including multiple forms of epilepsy, nonsyndromic intellectual disability, and movement disorders.STXBP1mutations have recently been associated with mitochondrial pathology, although it remains unclear if this phenotype is a part of the core feature for this gene disorder. We report a 7-year-old boy who presented for diagnostic evaluation of intractable epilepsy, episodic ataxia, resting tremor, and speech regression following a period of apparently normal early development. Mild lactic acidemia was detected on one occasion at the time of an intercurrent illness. Due to the concern for mitochondrial disease, ophthalmologic evaluation was performed that revealed bilateral midperiphery pigmentary mottling. Optical coherence tomography (OCT) testing demonstrated a bilaterally thickened ganglion cell layer in the perifovea. Skeletal muscle biopsy analysis showed no mitochondrial abnormalities or respiratory chain dysfunction. Exome sequencing identified ade novoc.1651C>T (p.R551C) mutation inSTXBP1.Although mitochondrial dysfunction has been reported in some individuals, our proband had only mild lactic acidemia and no skeletal muscle tissue evidence of mitochondrial disease pathology. Thus, mitochondrial dysfunction is not an obligate feature ofSTXBP1disease.
- Published
- 2016
94. Pallor and Lethargy in a 19-Month-Old Boy
- Author
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Fred M. Henretig, Elizabeth J. Bhoj, and Vijay Bhoj
- Subjects
Lethargy ,Male ,medicine.medical_specialty ,business.industry ,Infant ,General Medicine ,Dermatology ,Pallor ,Diagnosis, Differential ,Glucosephosphate Dehydrogenase Deficiency ,Insect Repellents ,Pediatrics, Perinatology and Child Health ,Emergency Medicine ,medicine ,Humans ,medicine.symptom ,business - Published
- 2014
95. Cerebro-costo-mandibular syndrome: Clinical, radiological, and genetic findings
- Author
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Francois P. Bernier, Sarah F. Smithson, Danielle C. Lynch, C Wallis, Debbie Shears, Jenny Morton, Elaine H. Zackai, Melissa Lees, Amaka C. Offiah, Usha Kini, Angela Barnicoat, Nobue Itasaki, Emma Wakeling, Tom Hilliard, Jillian S. Parboosingh, Jill Clayton-Smith, Alistair Calder, Simon Langton-Hewer, Angus John Clarke, Rebecca Hewitson, Elizabeth J. Bhoj, Richard H Scott, Madeleine J. Tooley, Michael Saunders, Tessa Homfray, Moira Blyth, and Peter Davis
- Subjects
0301 basic medicine ,Male ,Microcephaly ,Pathology ,medicine.medical_specialty ,Adolescent ,Micrognathism ,Ribs ,Scoliosis ,030105 genetics & heredity ,snRNP Core Proteins ,03 medical and health sciences ,Intellectual Disability ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Craniofacial ,Child ,Genetics (clinical) ,Rib cage ,Respiratory distress ,business.industry ,Hyoid bone ,Horseshoe kidney ,Infant ,Exons ,medicine.disease ,Cleft Palate ,030104 developmental biology ,Child, Preschool ,Mutation ,Pierre Robin syndrome ,Spliceosomes ,Female ,business - Abstract
Cerebro-Costo-Mandibular syndrome (CCMS) is a rare autosomal dominant condition comprising branchial arch-derivative malformations with striking rib-gaps. Affected patients often have respiratory difficulties, associated with upper airway obstruction, reduced thoracic capacity, and scoliosis. We describe a series of 12 sporadic and 4 familial patients including 13 infants/children and 3 adults. Severe micrognathia and reduced numbers of ribs with gaps are consistent findings. Cleft palate, feeding difficulties, respiratory distress, tracheostomy requirement, and scoliosis are common. Additional malformations such as horseshoe kidney, hypospadias, and septal heart defect may occur. Microcephaly and significant developmental delay are present in a small minority of patients. Key radiological findings are of a narrow thorax, multiple posterior rib gaps and abnormal costo-transverse articulation. A novel finding in 2 patients is bilateral accessory ossicles arising from the hyoid bone. Recently, specific mutations in SNRPB, which encodes components of the major spliceosome, have been found to cause CCMS. These mutations cluster in an alternatively spliced regulatory exon and result in altered SNRPB expression. DNA was available from 14 patients and SNRPB mutations were identified in 12 (4 previously reported). Eleven had recurrent mutations previously described in patients with CCMS and one had a novel mutation in the alternative exon. These results confirm the specificity of SNRPB mutations in CCMS and provide further evidence for the role of spliceosomal proteins in craniofacial and thoracic development.
- Published
- 2015
96. Maternal uniparental disomy of chromosome 20: a novel imprinting disorder of growth failure
- Author
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Karen W. Gripp, Elizabeth J. Bhoj, Claire L. S. Turner, Holly Dubbs, Miriam Elbracht, Nancy B. Spinner, Nina Powell-Hamilton, Laura K. Conlin, I. Karen Temple, Kim Jenny, David A. Stevenson, Elaine H. Zackai, Thomas Eggermann, Leah Slattery, Surabhi Mulchandani, Deborah J G Mackay, Ian D. Krantz, and Minjie Luo
- Subjects
0301 basic medicine ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Genotype ,Chromosomes, Human, Pair 20 ,Biology ,Short stature ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Genomic Imprinting ,medicine ,Humans ,Child ,Genetics (clinical) ,Growth Disorders ,Oligonucleotide Array Sequence Analysis ,Genetics ,Human Growth Hormone ,Mosaicism ,Meiosis II ,Facies ,Infant ,Uniparental Disomy ,medicine.disease ,Uniparental disomy ,030104 developmental biology ,Phenotype ,Nondisjunction ,Child, Preschool ,Failure to thrive ,Female ,Chromosome 20 ,medicine.symptom ,Trisomy ,Genomic imprinting ,Microsatellite Repeats - Abstract
Purpose:Maternal uniparental disomy of chromosome 20 (UPD(20)mat) has been reported in only four patients, three of whom also had mosaicism for complete or partial trisomy of chromosome 20. We sought to evaluate the clinical significance of isolated UPD(20)mat in eight individuals.Methods:We evaluated phenotypic and genomic findings of a series of eight new patients with UPD(20)mat.Results:All eight individuals with UPD(20)mat had intrauterine growth restriction, short stature, and prominent feeding difficulties with failure to thrive. As a common feature, they often required gastric tube feeds. Genomic data in most patients are indicative of UPD as a result of trisomy rescue after meiosis II nondisjunction.Conclusion:We describe the first natural history of the disorder and the results of therapeutic interventions, including the frequent requirement of direct gastric feedings only during the first few years of life, and propose that growth hormone supplementation is probably safe and effective for this condition. We suggest that UPD(20)mat can be regarded as a new imprinting disorder and its identification requires specialized molecular testing, which should be performed in patients with early-onset idiopathic isolated growth failure.
- Published
- 2015
97. Expanding the SPECC1L mutation phenotypic spectrum to include Teebi hypertelorism syndrome
- Author
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Margaret Harr, Dong Li, Elizabeth J. Bhoj, Hakon Hakonarson, Tiancheng Wang, Cecilia Kim, Haijun Qiu, Jodi D. Hoffman, Elaine H. Zackai, Yan Zhao, and Lifeng Tian
- Subjects
Male ,Adolescent ,Foot Deformities, Congenital ,DNA Mutational Analysis ,Molecular Sequence Data ,Biology ,Craniosynostosis ,Craniofacial Abnormalities ,Ptosis ,Genetics ,medicine ,Missense mutation ,Humans ,Abnormalities, Multiple ,Family ,Hypertelorism ,Child ,Genetics (clinical) ,Coronal craniosynostosis ,Base Sequence ,Infant, Newborn ,Shawl scrotum ,Facies ,Infant ,Anatomy ,Opitz G/BBB Syndrome ,medicine.disease ,Phosphoproteins ,Umbilical hernia ,Phenotype ,Child, Preschool ,Mutation ,medicine.symptom ,Hand Deformities, Congenital - Abstract
Teebi hypertelorism syndrome is a rare autosomal dominant disorder that has eluded a molecular etiology since first described in 1987. Here we report on two unrelated families with a Teebi hypertelorism-like syndrome and Teebi hypertelorism phenotype who have missense mutations in Sperm Antigen With Calponin Homology And Coiled-Coil Domains (SPECC1L), previously associated with oblique facial clefting and Opitz G/BBB syndrome. The first patient and his affected mother were previously-reported by Hoffman et al. in this journal as a new syndrome resembling Teebi hypertelorism and Aarskog syndromes in 2007. This patient had hypertelorism, sagittal and coronal craniosynostosis, ptosis, natal teeth, unusual umbilicus, shawl scrotum, small hands, and feet, with grossly normal development. Our second patient had classic Teebi hypertelorism syndrome with hypertelorism and a giant umbilical hernia. Patient one and his affected mother had a c.1260G>C:p.E420D variant and patient two had a de novo c.1198_1203delATACAC:p.I400_H401del variant in SPECC1L. We review the phenotypic findings in the previously-published Teebi hypertelorism syndrome patients, and the Opitz G/BBB patients with SPECC1L mutations. In addition we emphasize the findings of aortic root dilation and craniosynostosis in these patients, which should be considered in their management.
- Published
- 2015
98. Phenotypic Modifications of Patients with Full Chromosome Aneuploidies and Concurrent Suspected or Confirmed Second Diagnoses
- Author
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G. Bradley Schaefer, Lois J. Starr, Katherine A. Bosanko, Rebecca D. Ganetzky, Elaine H. Zackai, Yuri A. Zarate, and Elizabeth J. Bhoj
- Subjects
Marfan syndrome ,Male ,Down syndrome ,Pediatrics ,medicine.medical_specialty ,Aneuploidy ,Chromosome Disorders ,Comorbidity ,Biology ,Article ,Congenital Abnormalities ,Craniofacial microsomia ,Turner syndrome ,Genetics ,medicine ,Humans ,Medical diagnosis ,Child ,Genetics (clinical) ,Chromosome Aberrations ,Genetic Diseases, Inborn ,Infant, Newborn ,Chromosome ,Infant ,medicine.disease ,Phenotype ,Child, Preschool ,Female - Abstract
The coexistence of two or more distinct genetic conditions is known to be a rare phenomenon. Full chromosome aneuploidies can be associated with a broad variety of cytogenetic abnormalities or single gene disorders resulting in phenotypic modifications that confuse the diagnostic process. We present six patients with primary aneuploidies and a suspected or confirmed secondary genetic diagnosis or unusual birth defect. Among the cases included, we report the first patients with concurrent Down syndrome in combination with Prader-Willi, Craniofacial Microsomia, and Stickler syndromes. We also describe only the second reported case of a neonate with Down syndrome and Marfan syndrome. In all cases, the unusual clinical presentations lead to further molecular cytogenetic studies as well as single or multi-gene molecular evaluations. We make emphasis on the importance of entertaining the possibility of coexistent diagnoses when the phenotype is not what is expected for aneuploidies rather than attributing the unusual findings to rare or unreported associations of the primary aneuploidy.
- Published
- 2015
99. 'CHARGE-like presentation, craniosynostosis and mild Mowat-Wilson Syndrome diagnosed by recognition of the distinctive facial gestalt in a cohort of 28 new cases' American Journal of Medical Genetics Part A. 164:2557-2566, 2014
- Author
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Silvia Romano, Elizabeth J. Bhoj, Stefania Bigoni, Baris Malbora, Giovanni Sorge, Elena Andreucci, Livia Garavelli, Domenica Battaglia, Rebecca D. Ganetzky, Salvatore Savasta, Francesca Mari, Margaret P. Adam, Angelo Selicorni, Avni Santani, Margaret Harr, Tara L. Wenger, Guido Cocchi, Giuseppe Marangi, Sarah S. Barnett, Marcella Zollino, Donna M. McDonald-McGinn, Matteo Della Monica, Elaine H. Zackai, and Stefania Ricciardi
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Mowat–Wilson syndrome ,MEDLINE ,medicine.disease ,Craniosynostosis ,Settore MED/39 - NEUROPSICHIATRIA INFANTILE ,Cohort ,Genetics ,Medicine ,Medical genetics ,Gestalt psychology ,Presentation (obstetrics) ,business ,CHARGE ,Genetics (clinical) - Published
- 2015
100. Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome
- Author
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Bernard N. Chodirker, Jeremy Schwartzentruber, Care Rare Canada, A. Micheil Innes, Jillian S. Parboosingh, Danielle C. Lynch, D. Ross McLeod, Loydie A. Jerome-Majewska, Edwin P. Kirk, Ryan E. Lamont, Edmond G. Lemire, Jacek Majewski, Julie Hoover-Fong, Elizabeth J. Bhoj, Leah Fleming, Francois P. Bernier, Timothée Revil, Elaine H. Zackai, Juliet P. Taylor, and Ravi Savarirayan
- Subjects
Spliceosome ,RNA Stability ,Micrognathism ,General Physics and Astronomy ,Ribs ,Biology ,Bioinformatics ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Article ,snRNP Core Proteins ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Intellectual Disability ,medicine ,Humans ,Gene ,030304 developmental biology ,Genetics ,Regulation of gene expression ,0303 health sciences ,Mutation ,Multidisciplinary ,SnRNP Core Proteins ,Alternative splicing ,Exons ,General Chemistry ,3. Good health ,Alternative Splicing ,Gene Expression Regulation ,Regulatory sequence ,030217 neurology & neurosurgery - Abstract
Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro–costo–mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development., Cerebro–costo–mandibular syndrome, CCMS, is a severe human multiple malformation disorder. Here, the authors report that mutations in SNRPB disrupt the normal regulation of alternative splicing at this gene, and in so doing, may be responsible for the development of CCMS.
- Published
- 2014
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