76 results on '"Samantha A. Schrier Vergano"'
Search Results
2. Coffin-Siris syndrome and cancer susceptibility
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Nicholas A. Borja, Samantha A. Schrier Vergano, and Mustafa Tekin
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ARID1A ,ARID1B ,BAF-complex ,Cancer susceptibility ,Coffin-Siris syndrome ,Genetics ,QH426-470 ,Medicine - Abstract
Coffin-Siris syndrome (CSS) is a rare neurodevelopmental disorder that is associated with multiple congenital anomalies and caused by de novo monoallelic germline pathogenic variants in BAF-complex genes. Despite their function as tumor suppressors, the cancer risk in patients with CSS remains unclear. We analyzed cancer sequencing data sets, conducted a comprehensive literature review of patients with CSS diagnosed with malignancies, and examined a cohort of 376 CSS registry patients to estimate cancer frequency. A review of the literature identified several reports of patients with CSS diagnosed with a malignancy, with ARID1A being the most frequent causative gene and associated with hepatoblastoma in 3 cases. Although no cases of malignancy were reported among the patients in the CSS registry, only 26 patients with ARID1A-CSS were available for analysis. Combining these patients with all cases reported in the literature led to the estimate of hepatoblastoma prevalence in ARID1A-CSS of 3.6% (95% CI 0.79%-10.4%). Our findings suggest the hepatoblastoma risk among patients with ARID1A-CSS may exceed the established 1% risk threshold and therefore warrant surveillance. There remains insufficient evidence to support any other CSS gene-cancer association, emphasizing the need for further systematic study.
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- 2023
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3. EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum
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Ulrike Hüffmeier, Cornelia Kraus, Miriam S. Reuter, Steffen Uebe, Mary-Alice Abbott, Syed A. Ahmed, Kristyn L. Rawson, Eileen Barr, Hong Li, Ange-Line Bruel, Laurence Faivre, Frédéric Tran Mau-Them, Christina Botti, Susan Brooks, Kaitlyn Burns, D. Isum Ward, Marina Dutra-Clarke, Julian A. Martinez-Agosto, Hane Lee, Stanley F. Nelson, UCLA California Center for Rare Disease, Pia Zacher, Rami Abou Jamra, Chiara Klöckner, Julie McGaughran, Jürgen Kohlhase, Sarah Schuhmann, Ellen Moran, John Pappas, Annick Raas-Rothschild, Maria J. Guillen Sacoto, Lindsay B. Henderson, Timothy Blake Palculict, Sureni V. Mullegama, Houda Zghal Elloumi, Adi Reich, Samantha A. Schrier Vergano, Erica Wahl, André Reis, and Christiane Zweier
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EIF3F gene ,Neurodevelopmental disorder ,Short stature ,Deafness ,Behavioral difficulties ,Altered muscular tone ,Medicine - Abstract
Abstract Background An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients. Results 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals’ facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype–phenotype correlation. Conclusions Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.
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- 2021
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4. Expanding the clinical and phenotypic heterogeneity associated with biallelic variants in ACO2
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Patrick R. Blackburn, Matthew J. Schultz, Carrie A. Lahner, Dong Li, Elizabeth Bhoj, Laura J. Fisher, Deborah L. Renaud, Amy Kenney, Niema Ibrahim, Mais Hashem, Mohammed Zain Seidahmed, Linda Hasadsri, Samantha A. Schrier Vergano, Fowzan S. Alkuraya, and Brendan C. Lanpher
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
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
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5. Language Impairments in Individuals With Coffin-Siris Syndrome
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Ashley Vasko and Samantha A. Schrier Vergano
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Coffin-Siris syndrome (CSS) ,language ,BAF complex ,intellectual and developmental disabilities ,speech ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Coffin-Siris syndrome (CSS, MIM 135900) is a now well-described, multiple congenital anomaly/intellectual disability syndrome classically characterized by fifth digit/nail hypoplasia, coarse facial features, and a range of organ-system related anomalies. Since its initial description in 1970, and the discovery of associated genes in 2011, CSS now encompasses a wide range of phenotypes and abilities caused by pathogenic variants in the BAF complex (often referred to as “BAFopathy”). It appears that the BAF complex leads to speech and language impairments in this population, and subsequently we have reviewed individuals in the CSS/BAF registry to understand the prevalence and degree of this particular learning difference. We have examined the frequency of delayed language acquisition, augmented communication device use, and speech intervention therapies. To aid in language progression, childhood speech interventions are necessary in children with a diagnosis of CSS. While the majority of children with pathogenic variants in the BAF complex have language-related struggles, the exact mechanism is not yet fully understood. At the time of writing, there are 284 individuals in the CSS/BAF registry with known variants in the following genes; ARID1B (n = 174), SMARCA4 (n = 41), ARID1A (n = 20), SMARCB1 (n = 20), ARID2 (n = 14), SOX11 (n = 10), and SMARCE1 (n = 5). While speech delays in individuals with CSS are expected, a full analysis of these delays has yet to be detailed. In the CSS/BAF registry, we identified 183 (64%) individuals with language-related challenges and 90 (32%) individuals that are non-verbal.
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- 2022
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6. Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms
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Megan Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei, Kathryn Elliott, Dana H. Goodloe, S. Joy Dean, Catherine Gooch, Brianna K. Murray, Erin Swartz, Samantha A. Schrier Vergano, Meghan C. Towne, Kimberly Nugent, Elizabeth R. Roeder, Christina Kresge, Beth A. Pletcher, Katheryn Grand, John M. Graham Jr., Ryan Gates, Natalia Gomez‐Ospina, Subhadra Ramanathan, Robin Dawn Clark, Kimberly Glaser, Paul J. Benke, Julie S. Cohen, Ali Fatemi, Weiyi Mu, Kristin W. Baranano, Jill A. Madden, Cynthia S. Gubbels, Timothy W. Yu, Pankaj B. Agrawal, Mary‐Kathryn Chambers, Chanika Phornphutkul, John A. Pugh, Kate A. Tauber, Svetlana Azova, Jessica R. Smith, Anne O’Donnell‐Luria, Hannah Medsker, Siddharth Srivastava, Deborah Krakow, Daniela N. Schweitzer, and Valerie A. Arboleda
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CRISPR ,Genitopatellar syndrome ,KAT6B‐related disorders ,phenotypic spectrum ,Say‐Barber‐Biesecker‐Young‐Simpson syndrome ,variable expressivity, rare genetic diagnosis ,Genetics ,QH426-470 - Abstract
Abstract The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say‐Barber‐Biesecker‐Young‐Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B‐related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B‐related disorders.
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- 2021
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7. Previously Unidentified Gene Variation Associated with Fabry Disease: The Impact on One Family
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Amaresh R. Vanga, Samantha A. Schrier Vergano, Jolanta Kowalewska, and Thomas R. McCune
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Fabry disease is an X-linked lysosomal storage genetic disorder associated with over 1000 mutations in the alpha-galactosidase-A gene region. We report here a 69-year-old male who underwent a kidney biopsy to evaluate progressive renal failure. He was found to have zebra bodies in visceral epithelial cells on biopsy, with electron microscopy showing inclusions within the cytoplasm of multiple podocytes consistent with Fabry disease. An alpha-galactosidase level was found to be 21 nm/hr/mg (normal range 50–150 nm/hr/mg). Genetic studies revealed a missense variant in the GLA gene with alanine replaced by cysteine at position 682 (c.682 A > C, p.N228H) that had not been previously associated with Fabry disease. The same variant was detected in two additional family members. The pathologic findings, clinical features, and low alpha-galactosidase level suggest that the c.682 A > C variant is associated with Fabry disease.
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- 2020
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8. Addressing underrepresentation in genomics research through community engagement
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Amy A. Lemke, Edward D. Esplin, Aaron J. Goldenberg, Claudia Gonzaga-Jauregui, Neil A. Hanchard, Julie Harris-Wai, Justin E. Ideozu, Rosario Isasi, Andrew P. Landstrom, Anya E.R. Prince, Erin Turbitt, Maya Sabatello, Samantha A. Schrier Vergano, Matthew R.G. Taylor, Joon-Ho Yu, Kyle B. Brothers, and Nanibaa’ A. Garrison
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Genetics & Heredity ,06 Biological Sciences, 11 Medical and Health Sciences ,Genetics ,Humans ,Genomics ,ASHG Guidance ,Research Personnel ,United States ,Genetics (clinical) - Abstract
The vision of the American Society of Human Genetics (ASHG) is that people everywhere will realize the benefits of human genetics and genomics. Implicit in that vision is the importance of ensuring that the benefits of human genetics and genomics research are realized in ways that minimize harms and maximize benefits, a goal that can only be achieved through focused efforts to address health inequities and increase the representation of underrepresented communities in genetics and genomics research. This guidance is intended to advance community engagement as an approach that can be used across the research lifecycle. Community engagement uniquely offers researchers in human genetics and genomics an opportunity to pursue that vision successfully, including by addressing underrepresentation in genomics research.
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- 2022
9. Evidence for an association between <scp>Coffin‐Siris</scp> syndrome and congenital diaphragmatic hernia
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Yoel Gofin, Xiaonan Zhao, Amanda Gerard, Fernando Scaglia, Michael F. Wangler, Samantha A. Schrier Vergano, and Daryl A. Scott
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Genetics ,Genetics (clinical) - Published
- 2022
10. Heterozygous variants in PRPF8 are associated with neurodevelopmental disorders
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Lauren O'Grady, Samantha A. Schrier Vergano, Trevor L. Hoffman, Dean Sarco, Sara Cherny, Emily Bryant, Laura Schultz‐Rogers, Wendy K. Chung, Stephanie Sacharow, Ladonna L. Immken, Susan Holder, Rebecca R. Blackwell, Catherine Buchanan, Roman Yusupov, François Lecoquierre, Anne‐Marie Guerrot, Lance Rodan, Bert B. A. de Vries, Erik Jan Kamsteeg, Fernando Santos Simarro, Maria Palomares‐Bralo, Natasha Brown, Lynn Pais, Alejandro Ferrer, Eric W. Klee, Dusica Babovic‐Vuksanovic, Lindsay Rhodes, Richard Person, Amber Begtrup, Jennifer Keller‐Ramey, Teresa Santiago‐Sim, Rhonda E. Schnur, David A. Sweetser, and Nina B. Gold
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Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Genetics ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Genetics (clinical) - Abstract
Contains fulltext : 282684.pdf (Publisher’s version ) (Closed access) The pre-mRNA-processing factor 8, encoded by PRPF8, is a scaffolding component of a spliceosome complex involved in the removal of introns from mRNA precursors. Previously, heterozygous pathogenic variants in PRPF8 have been associated with autosomal dominant retinitis pigmentosa. More recently, PRPF8 was suggested as a candidate gene for autism spectrum disorder due to the enrichment of sequence variants in this gene in individuals with neurodevelopmental disorders. We report 14 individuals with various forms of neurodevelopmental conditions, found to have heterozygous, predominantly de novo, missense, and loss-of-function variants in PRPF8. These individuals have clinical features that may represent a new neurodevelopmental syndrome.
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- 2022
11. Rare Cause of Arrhythmia and Seizures in a Late-Preterm Newborn
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Priya, Tiwari, Katerina, Dwyer, Brett, Siegfried, and Samantha A, Schrier Vergano
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Seizures ,Pediatrics, Perinatology and Child Health ,Infant, Newborn ,Humans ,Premature Birth ,Arrhythmias, Cardiac ,Female - Published
- 2022
12. Exome and <scp>RNA‐Seq</scp> analyses of an incomplete penetrance variant in <scp> USP9X </scp> in female‐specific syndromic intellectual disability
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Dong Li, Michael E. March, Tiancheng Wang, Victoria Merengwa, Livia Sertori Finoti, Samantha A. Schrier Vergano, Hakon Hakonarson, and Elizabeth J. Bhoj
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Male ,Intellectual Disability ,Exome Sequencing ,Genetics ,Humans ,Exome ,Female ,Penetrance ,RNA-Seq ,Ubiquitin Thiolesterase ,Genetics (clinical) - Abstract
Pathogenic variants in USP9X, on X chromosome, have been implicated in syndromic intellectual disability (ID) in both males and females with distinct craniofacial features. We report a truncating variant, c.885_889delAAAAG, p.(Lys296Serfs*4), in the USP9X gene with incomplete penetrance in two nontwin female siblings with phenotypic resemblance to female-specific syndromic ID (MIM 300969, also known as MRX99F). To investigate the possible genetic etiology of the reduced penetrance, X-inactivation, RNA-Seq, and full quad exome analyses were attempted, but failed to identify a promising candidate modifier. While the penetrance of pathogenic variants in USP9X in female appears to be high (95%) and the variants frequently occur de novo, incomplete penetrance should be considered.
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- 2022
13. Expanding the phenotype of <scp> ASXL3 </scp> ‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in <scp> ASXL3 </scp>
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Katherine Bergstrom, Nichola Foulds, Yue Si, Anne Slavotinek, John Dean, Evan Reid, Ruth Armstrong, Charlotte W. Ockeloen, Richard Fisher, Maria J. Guillen Sacoto, Dayna Morel, Fowzan S. Alkuraya, Costa Cinzia, Thomas D. Challman, Samantha A. Schrier Vergano, Francisca Milan Zamora, Naomi Meeks, John Pappas, Katheryn Grand, Abhijit Dixit, Julie S. Cohen, Ddd Study, Marjolein H. Willemsen, Serwet Demirdas, Rachel Harrison, Usha Kini, Bertrand Isidor, Patricia Blanchet, Emily Palen, Arjan Bouman, Jagdeep S. Walia, Ruth Newbury-Ecob, Rachel Rabin, Shadi Albaba, Diana Johnson, Paolo Prontera, Paula Girotto, Ange-Line Bruel, Meena Balasubramanian, Nicola K. Ragge, Schaida Schirwani, Deborah L. Renaud, Christopher Cunniff, John M. Graham, Natalie Dykzeul, Swati Naik, Valerie Slegesky, Hessa F Albassam, Maria Giovanna Tedesco, Sally Ann Lynch, Julie Vogt, Natalie Hauser, Dong Li, Deanna Alexis Carere, and Benjamin Cogné
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Genetics ,Biology ,medicine.disease ,Phenotype ,Hypotonia ,Natural history ,Neurodevelopmental disorder ,Intellectual disability ,medicine ,Missense mutation ,Hypertelorism ,medicine.symptom ,Genetics (clinical) ,Sequence (medicine) - Abstract
The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.
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- 2021
14. Inborn Errors of Metabolism: Becoming Ready for Rare
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Samantha A. Schrier Vergano
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Galactosemias ,Lysosomal Storage Diseases ,Pediatrics, Perinatology and Child Health ,Infant, Newborn ,Humans ,Infant ,Child ,Glycogen Storage Disease ,Amino Acid Metabolism, Inborn Errors ,Metabolism, Inborn Errors - Abstract
Inborn errors of metabolism (IEMs) are a large group of disorders that can present in any age group and must be considered in the differential diagnosis for a variety of signs and symptoms appearing in infants and children. The rarity and complexity of these conditions often make them difficult to recognize, as they may mimic more common conditions. This review article discusses some of the more commonly presenting IEMs that are important for the general pediatrician to understand when evaluating a sick patient. Many of these diseases are also on the newborn screen, which pediatricians often encounter as first-line providers. Disorders that are discussed in detail herein include disorders of amino acid metabolism, including amino acidopathies and organic acidurias; urea cycle disorders; defects in fatty acid β-oxidation; disorders of carbohydrate metabolism, including the glycogen storage diseases and galactosemia; and lysosomal storage diseases.
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- 2022
15. De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females
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Eugênia Ribeiro Valadares, Kaitlyn M Shen, Sérgio D.J. Pena, Alanna Strong, Dong Li, Natália D. Linhares, David Cassiman, Elaine H. Zackai, Deindl Philipp, Penny Chow, Arupa Ganguly, Jaak Jaeken, Samantha A. Schrier Vergano, Maria Van Dyck, Tatjana Bierhals, Tiancheng Wang, Elizabeth J. Bhoj, Hakon Hakonarson, Anne Hing, and Tasja Scholz
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0301 basic medicine ,Genetics ,business.industry ,media_common.quotation_subject ,Nonsense ,030105 genetics & heredity ,medicine.disease ,Frameshift mutation ,MED12 ,03 medical and health sciences ,030104 developmental biology ,Intestinal malrotation ,Intellectual disability ,medicine ,Missense mutation ,business ,Genetics (clinical) ,Exome sequencing ,Loss function ,media_common - Abstract
Purpose Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder. Methods We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed. Results We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing. Conclusion Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.
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- 2021
16. Variants in GNAI1 Cause a Syndrome Associated with Variable Features including Developmental Delay, Seizures and Hypotonia
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Lauren Brady, Bryan E. Hainline, Konrad Platzer, Muhammad Zafar, Corinna Powell, Darcy J. Huismann, Heather C Mefford, Afnan Alhakeem, Daniel G. MacArthur, Alison M. Muir, Trevor L Hoffman, Mark A. Tarnopolsky, François Lecoquierre, Lindsay Rhodes, Tilman Polster, Susanne Axer-Schaefer, Alice Goldenberg, Katherine Sapp, Caoimhe S. McKenna, Jasper J. van der Smagt, Tara Montgomery, Eleina M. England, Brianna K. Murray, Myriam Srour, Lia Zitano, William B. Dobyns, Grace Noh, Angela F. Brady, Lindsey Sawyer, Ingrid M. Wentzensen, Holly Dubbs, Jane Juusola, Richard Caswell, Richard H. van Jaarsveld, Danielle DeMarzo, Samantha A. Schrier Vergano, Caleb Bupp, Grace E. VanNoy, Jose E. Martinez, Melanie O’Leary, Iris M de Lange, Shane McKee, Golder N. Wilson, Rhonda E. Schnur, Meira Meltzer, Vinod Varghese, Kristin G. Monaghan, Carole Brewer, Carolyn Tysoe, Jennifer F. Gardner, Ethan M. Goldberg, Shelagh Joss, Andrea Accogli, Chiara Klöckner, Andrea L. Gropman, and Pradeep C. Vasudevan
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0301 basic medicine ,Developmental Disabilities ,030105 genetics & heredity ,Biology ,Article ,03 medical and health sciences ,Epilepsy ,Neurodevelopmental disorder ,Seizures ,Intellectual Disability ,Intellectual disability ,Exome Sequencing ,medicine ,Humans ,Global developmental delay ,Child ,Genetics (clinical) ,Exome sequencing ,Genetics ,Genetic heterogeneity ,medicine.disease ,Hypotonia ,030104 developmental biology ,Neurodevelopmental Disorders ,Autism ,Muscle Hypotonia ,medicine.symptom - Abstract
Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and one was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
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- 2021
17. Author Response
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Samantha A. Schrier Vergano
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Pediatrics, Perinatology and Child Health - Published
- 2022
18. Growth charts for individuals with <scp>Coffin‐Siris</scp> syndrome
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Rajan Lamichhane, Nicole Holt, Emily A. McCague, and Samantha A. Schrier Vergano
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Male ,Pediatrics ,medicine.medical_specialty ,Micrognathism ,Population ,Growth hormone ,Short stature ,Intellectual Disability ,Chart review ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,Growth Charts ,Child ,education ,Coffin–Siris syndrome ,Genetic Association Studies ,Genetics (clinical) ,education.field_of_study ,business.industry ,DNA Helicases ,Infant, Newborn ,Infant ,Nuclear Proteins ,Anthropometry ,medicine.disease ,Child, Preschool ,Face ,Cohort ,Failure to thrive ,Female ,medicine.symptom ,business ,Hand Deformities, Congenital ,Neck ,Transcription Factors - Abstract
Coffin-Siris syndrome (CSS; OMIM #135900) is a rare, multisystem syndrome caused by pathogenic variants in genes encoding the BRG-1 associated factors complex (BAF). Individuals with CSS often present with feeding difficulties and failure to thrive during infancy, in addition to a number of variable congenital anomalies. Nutritional interventions are used to support growth in this population, and growth hormone therapy has been reported in a limited number of cases. The purpose of this study was to construct CSS-specific growth charts to better characterize the growth in this population. Anthropometric data were collected from 99 individuals enrolled in the CSS/BAF pathway international registry via a retrospective chart review. All measurements obtained after the first exposure to growth hormone therapy were excluded from this analysis. Sex-specific centiles (5th, 50th, and 95th) were estimated for height, weight, and head circumference from birth to age 10. Cubic smoothing splines were then fit to the centile estimates and superimposed on normative male and female growth curves for comparison. The CSS patients in this cohort exhibited normal growth parameters at birth. By age 10, the weight and head circumference of the CSS cohort began to approach normal parameters. Stature, however, remained shortened at 10 years of age.
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- 2020
19. Making Decisions About Krabbe Disease Newborn Screening
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Samantha A. Schrier Vergano, Shibani Kanungo, and Georgianne Arnold
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Neonatal Screening ,Pediatrics, Perinatology and Child Health ,Decision Making ,Infant, Newborn ,Humans ,Leukodystrophy, Globoid Cell - Published
- 2022
20. Absent Red Reflexes and Cloudy Corneas
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Eric R. Crouch, W. Thomas Bass, Samantha A. Schrier Vergano, Sina Vahedi, and Diem-Anh Vo
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medicine.medical_specialty ,business.industry ,Corneal opacity ,Cornea ,Red reflex ,medicine.anatomical_structure ,Cloudy corneas ,Ophthalmology ,Pediatrics, Perinatology and Child Health ,medicine ,Reflex ,Humans ,business - Published
- 2021
21. Further supporting SMARCC2-related neurodevelopmental disorder through exome analysis and reanalysis in two patients
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Dong Li, Helen Downes, Cuiping Hou, Hakon Hakonarson, Elaine H. Zackai, Samantha A. Schrier Vergano, and Elizabeth J. Bhoj
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DNA-Binding Proteins ,Phenotype ,Neurodevelopmental Disorders ,Intellectual Disability ,Mutation ,Genetics ,Humans ,Abnormalities, Multiple ,Exome ,Genetics (clinical) ,Transcription Factors - Abstract
BAFopathies are a heterogenous group of neurodevelopmental disorders caused by mutations in genes encoding subunits of the BAF complex, and they exhibit a broad clinical phenotypic spectrum. Pathogenic heterozygous variants in SMARCC2 have been implicated in Coffin-Siris syndrome 8 (MIM 618362) with variable neurodevelopmental presentations. We report here two relatively severely affected patients with two different SMARCC2 variants: one has de novo pathogenic variant, c.1824_1826del, p.(Leu609del), in a suspected hotspot region through reanalysis of previously negative clinical exome data, and the other has a likely pathogenic loss-of-function variant, c.1094_1097delAGAA, p.(Lys365Thrfs*12) through exome analysis in an adopted subject. Regardless of variant type, both patients have severe developmental delays, severe speech delay, short stature, hypotonia, seizures, and craniofacial dysmorphisms, blurring previously speculated genotype-phenotype correlation on missense and loss-of-function variants. This report extends our understanding of the genotypic and phenotypic spectrums of the SMARCC2-related neurodevelopmental disorder.
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- 2021
22. Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms
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Kathryn Elliott, Siddharth Srivastava, Meghan C. Towne, Hannah Medsker, Catherine Gooch, Robin D. Clark, John M. Graham, Chanika Phornphutkul, Jill A. Madden, Pankaj B. Agrawal, Maria F. Palafox, Deborah Krakow, Meghna Singh, Daniela N. Schweitzer, Ryan Gates, Ali Fatemi, Kimberly Nugent, Katheryn Grand, Samantha A. Schrier Vergano, Brianna K. Murray, Kate A. Tauber, Weiyi Mu, Erin Swartz, Timothy W. Yu, Julie S. Cohen, Kimberly Glaser, Svetlana Azova, Paul J. Benke, Mary Kathryn Chambers, Dana H. Goodloe, Christina Kresge, Valerie A. Arboleda, John A. Pugh, Kristin W. Barañano, Megan Yabumoto, S. Joy Dean, Beth A. Pletcher, Subhadra Ramanathan, Angela Wei, Jessica Kianmahd, Elizabeth Roeder, Natalia Gomez-Ospina, Jessica Smith, Cynthia S. Gubbels, and Anne H. O’Donnell-Luria
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Male ,Say-Barber-Biesecker-Young-Simpson syndrome ,rare genetic diagnosis ,QH426-470 ,Bioinformatics ,Kidney ,Cohort Studies ,Craniofacial Abnormalities ,Congenital ,Intellectual disability ,Medicine ,CRISPR ,2.1 Biological and endogenous factors ,variable expressivity, rare genetic diagnosis ,Medical diagnosis ,Aetiology ,Genetics (clinical) ,Heart Defects ,Histone Acetyltransferases ,Pediatric ,Patella ,Phenotype ,Scrotum ,Original Article ,Abnormalities ,KAT6B-related disorders ,Multiple ,Heart Defects, Congenital ,Joint Instability ,Genitopatellar syndrome ,Genotype ,Genetic counseling ,Intellectual and Developmental Disabilities (IDD) ,Clinical Sciences ,Genetic Counseling ,Blepharophimosis ,Medicinal and Biomolecular Chemistry ,Rare Diseases ,Clinical Research ,variable expressivity ,Intellectual Disability ,Congenital Hypothyroidism ,Genetics ,Humans ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,Genetic Testing ,Craniofacial ,Molecular Biology ,Alleles ,Genetic Association Studies ,KAT6B‐related disorders ,business.industry ,Facies ,Original Articles ,medicine.disease ,Say‐Barber‐Biesecker‐Young‐Simpson syndrome ,Transcriptome Sequencing ,Brain Disorders ,Genetic Loci ,Urogenital Abnormalities ,Mutation ,Congenital Structural Anomalies ,Psychomotor Disorders ,business ,phenotypic spectrum - Abstract
The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say‐Barber‐Biesecker‐Young‐Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B‐related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B‐related disorders., We describe 20 new cases harboring the KAT6B spectrum of disorders, which range from Say‐Barber‐Biesecker‐Young‐Simpson (SBBYSS) to Genitopatellar (GPS) syndrome or an intermediate phenotype. In our holistic approach, we expand the genotypic and phenotypic spectrum of KAT6B spectrum of disorders. Furthermore, we provide extensive clinical phenotyping, explore the impact of genetic counseling for these complex syndromes, and examine molecular mechanisms in RNA‐seq data in an in vitro cell model of truncating KAT6B mutations.
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- 2021
23. Genotype-Phenotype Correlations in 208 Individuals with Coffin-Siris Syndrome
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Theodore G. Drivas, Samantha A. Schrier Vergano, and Ashley Vasko
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0301 basic medicine ,Hypertrichosis ,Genotype ,Micrognathism ,030105 genetics & heredity ,Biology ,QH426-470 ,Article ,03 medical and health sciences ,Intellectual Disability ,Intellectual disability ,medicine ,Genetics ,Humans ,Abnormalities, Multiple ,Coffin-Siris syndrome ,BAF complex ,Coffin–Siris syndrome ,Genetics (clinical) ,medicine.disease ,Phenotype ,Hypoplasia ,Hypotonia ,genotype-phenotype ,030104 developmental biology ,Face ,Mutation ,SMARCA4 ,medicine.symptom ,Hand Deformities, Congenital ,Neck ,Transcription Factors - Abstract
Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ system anomalies. Genes in the BRG1(BRM)-associated factors (BAF, Brahma associated factor) complex have been shown to be causative, including ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, and SOX4. In order to describe more robust genotype-phenotype correlations, we collected data from 208 individuals from the CSS/BAF complex registry with pathogenic variants in seven of these genes. Data were organized into cohorts by affected gene, comparing genotype groups across a number of binary and quantitative phenotypes. We determined that, while numerous phenotypes are seen in individuals with variants in the BAF complex, hypotonia, hypertrichosis, sparse scalp hair, and hypoplasia of the distal phalanx are still some of the most common features. It has been previously proposed that individuals with ARID-related variants are thought to have more learning and developmental struggles, and individuals with SMARC-related variants, while they also have developmental delay, tend to have more severe organ-related complications. SOX-related variants also have developmental differences and organ-related complications but are most associated with neurodevelopmental differences. While these generalizations still overall hold true, we have found that all individuals with BAF-related conditions are at risk of many aspects of the phenotype, and management and surveillance should be broad.
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- 2021
24. Case 2: Term Female Newborn with Prenatal Diagnosis of Abdominal Distention and Ascites
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Kevin J. Crow, Samantha A. Schrier Vergano, Rachel Glad, Jamil H. Khan, W. Thomas Bass, and Aisha Venugopal
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Polyhydramnios ,Amniotic fluid ,medicine.medical_treatment ,Prenatal diagnosis ,Physical examination ,Pregnancy ,Prenatal Diagnosis ,Abdomen ,Ascites ,medicine ,Humans ,Abnormalities, Multiple ,Continuous positive airway pressure ,medicine.diagnostic_test ,Vaginal delivery ,business.industry ,Infant, Newborn ,Toes ,medicine.disease ,Intestines ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Female ,medicine.symptom ,business ,Digestive System Abnormalities - Abstract
A 3,960-g female infant is born at 37 weeks of gestation to a 25-year-old gravida 2, para 1-0-0-1 woman via vaginal delivery. The pregnancy had been complicated by a history of depression not requiring pharmacologic treatment, a urinary tract infection treated successfully, fetal abdominal distention and ascites, and polyhydramnios requiring 3 procedures for amniotic fluid reduction. Noninvasive prenatal testing and α-fetoprotein levels were normal. Apgar scores are 6 and 8 at 1 and 5 minutes, respectively. The infant has decreased respiratory effort but improves with continuous positive airway pressure and is weaned to room air while in the delivery room with no further respiratory concerns. Because of the significant abdominal distention, the patient is transferred to the NICU where the physical examination findings are significant for abdominal distention, an abdominal circumference of 38 cm, palpable bowel loops, and absent bowel sounds. Other significant findings include bilateral webbing of the second and third toes and bilateral fusion of …
- Published
- 2020
25. Clinical spectrum of individuals with pathogenic N F1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype–phenotype study in neurofibromatosis type 1
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Giulio Piluso, Katharina Wimmer, Veronica Saletti, Eniko K. Pivnick, Geraldine Kelly-Mancuso, Karen W. Gripp, Cristin Griffis, Louanne Hudgins, Alessandro De Luca, Michael F. Wangler, M. Daniela D'Agostino, Marica Eoli, Cynthia M. Powell, Laura A. Baker, Mayra Martinez Ojeda, Silvia Esposito, Elizabeth A. Sellars, Kory Keller, David D. Weaver, James T. Bennett, Nicole J. Ullrich, Allison L. Goetsch, Donald Basel, Bruce R. Korf, Stephanie Fox, Katelyn Hodge, Laura Dosa, Robert S. Greenwood, Mario Bengala, Andrea M. Lewis, Ruth Sheffer, Valentina Pinna, Fanny Cortés, Dusica Babovic-Vuksanovic, Aaina Kochhar, Rosemarie Smith, Concepción Hernández-Chico, Elizabeth Siqveland, Robert Listernick, Lola K. Clarkson, Punita Gupta, E. Haan, Martin B. Delatycki, Amy Theos, Noa Ruhrman Shahar, Teresa Giugliano, Carey McDougall, Mitch Cunningham, David W. Stockton, Tom Callens, Maria Cristina Digilio, Yunjia Chen, Ludwine Messiaen, Eva Trevisson, Samantha A. Schrier Vergano, Caleb Rogers, Magdalena Koczkowska, Kathleen Claes, Christine Fauth, Jan Liebelt, Pamela Trapane, Eric Johns, John M. Slopis, Chelsea Chambers, Tamara L. Haygarth, Lesley K. McGregor, Alberto Spalice, Małgorzata J.M. Nowaczyk, Mary Ella M Pierpont, Kaleb Yohay, Alicia Gomes, Vickie Zurcher, Gail E. Tomlinson, Angie W. Lichty, Stephanie E Wallace, Rachel K. Hachen, Isabelle Maystadt, S. Lane Rutledge, Yael Goldberg, Grace Tran, Ulrich A. Schatz, Allison Schreiber, Jenneke van den Ende, Michael J. Lyons, Mary Louise Freckmann, Kim Armfield Uhas, Alesha D. Hicks, Maurizio Clementi, Haley Streff, June Ortenberg, John Pappas, Nancy J. Mendelsohn, Sandra Janssens, Karin Panzer, Yolanda Martin, Elaine H. Zackai, Sandra Giustini, Linlea Armstrong, Katherine A. Bosanko, Angela Sharp, Daryl A. Scott, Jonathan Zonana, Robert J. Hopkin, Eric Legius, Dinel A. Pond, Daniela Melis, Claudia Santoro, and Sarah A. Sandaradura
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congenital, hereditary, and neonatal diseases and abnormalities ,0303 health sciences ,medicine.medical_specialty ,education.field_of_study ,Pulmonic stenosis ,030305 genetics & heredity ,Population ,Spinal neurofibromas ,Biology ,medicine.disease ,Phenotype ,Gastroenterology ,nervous system diseases ,03 medical and health sciences ,Internal medicine ,Cohort ,Genetics ,medicine ,Missense mutation ,Noonan syndrome ,Neurofibromatosis ,education ,Genetics (clinical) ,030304 developmental biology - Abstract
We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
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- 2019
26. De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes
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Adelaide Rega, Y. T. Hu, Daniel Helbling, Sebastien Moutton, Anna C.E. Hurst, Qing Kenneth Wang, Grazia M.S. Mancini, Samantha A. Schrier Vergano, Chengqi Xu, Lina Liang, Xia Li, Bertrand Isidor, Christel Thauvin-Robinet, Laurence Faivre, Sophie Nambot, Christina Hung, Benjamin Cogné, Olaf Bodamer, Julien Thevenon, Leon S. Dure, David P. Bick, Yannis Duffourd, Bénédicte Gérard, Stéphane Bézieau, Antonio Vitobello, Qiuyun Chen, Anne de Saint-Martin, Daphné Lehalle, and Clinical Genetics
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Male ,Ataxia ,Genotype ,Developmental Disabilities ,Mutation, Missense ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Neurodevelopmental disorder ,Protein Domains ,Loss of Function Mutation ,Genetics ,medicine ,Humans ,Missense mutation ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,Protein Interaction Domains and Motifs ,Allele ,Large-Conductance Calcium-Activated Potassium Channel alpha Subunits ,Molecular Biology ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Loss function ,Exome sequencing ,030304 developmental biology ,0303 health sciences ,Infant, Newborn ,General Medicine ,Paroxysmal dyskinesia ,medicine.disease ,Electrophysiological Phenomena ,Pedigree ,Phenotype ,Amino Acid Substitution ,Speech delay ,Female ,General Article ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
KCNMA1 encodes the large-conductance Ca2+- and voltage-activated K+ (BK) potassium channel α-subunit, and pathogenic gain-of-function variants in this gene have been associated with a dominant form of generalized epilepsy and paroxysmal dyskinesia. Here, we genetically and functionally characterize eight novel loss-of-function (LoF) variants of KCNMA1. Genome or exome sequencing and the participation in the international Matchmaker Exchange effort allowed for the identification of novel KCNMA1 variants. Patch clamping was used to assess functionality of mutant BK channels. The KCNMA1 variants p.(Ser351Tyr), p.(Gly356Arg), p.(Gly375Arg), p.(Asn449fs) and p.(Ile663Val) abolished the BK current, whereas p.(Cys413Tyr) and p.(Pro805Leu) reduced the BK current amplitude and shifted the activation curves toward positive potentials. The p.(Asp984Asn) variant reduced the current amplitude without affecting kinetics. A phenotypic analysis of the patients carrying the recurrent p.(Gly375Arg) de novo missense LoF variant revealed a novel syndromic neurodevelopmental disorder associated with severe developmental delay, visceral and cardiac malformations, connective tissue presentations with arterial involvement, bone dysplasia and characteristic dysmorphic features. Patients with other LoF variants presented with neurological and developmental symptoms including developmental delay, intellectual disability, ataxia, axial hypotonia, cerebral atrophy and speech delay/apraxia/dysarthria. Therefore, LoF KCNMA1 variants are associated with a new syndrome characterized by a broad spectrum of neurological phenotypes and developmental disorders. LoF variants of KCNMA1 cause a new syndrome distinctly different from gain-of-function variants in the same gene.
- Published
- 2019
27. Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome
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Deborah A. Nickerson, Nivedita Patni, Dustin Baldridge, Marcia C. Willing, Anil K. Agarwal, Jennifer A. Wambach, Chao Xing, Samantha A. Schrier Vergano, Daniel J. Wegner, Michael J. Bamshad, Amy Kenney, Tasnim Najaf, Martin Kircher, F. Sessions Cole, Abhimanyu Garg, Dorothy K. Grange, and Chirag Patel
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Adult ,0301 basic medicine ,Adolescent ,Genotype ,Loss of Heterozygosity ,030105 genetics & heredity ,Biology ,RNA polymerase III ,Neonatal Progeroid Syndrome ,Young Adult ,03 medical and health sciences ,Progeria ,Hypogonadotropic hypogonadism ,Report ,Genetics ,medicine ,Humans ,Missense mutation ,Allele ,Alleles ,Genetics (clinical) ,Loss function ,Fetal Growth Retardation ,Genetic Variation ,RNA Polymerase III ,medicine.disease ,Phenotype ,030104 developmental biology ,Child, Preschool ,RNA splicing ,Female ,Lipodystrophy - Abstract
Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy.
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- 2018
28. 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
29. 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
30. 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
31. The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis
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Marie Falkenberg Smeland, Alina Kurolap, Michael J. Gambello, Ariel F. Martinez, Livija Medne, Melita Irving, Elizabeth Roeder, Holly Dubbs, Robert M. Petrovich, Elaine H. Zackai, Motoki Takaku, Kimberly Nugent, Bruce D. Gelb, Peter D. Turnpenny, Michael Parker, Maximilian Muenke, Thomas Smol, Arie van Haeringen, Hanne Hove, Hitoshi Kurumizaka, Sandra Whalen, Boris Keren, Philippe M. Campeau, Samantha A. Schrier Vergano, Lior Cohen, Pauline Terhal, Amy Kenney, Paul A. Wade, Jill Clayton-Smith, Jamal Ghoumid, Shane C. Quinonez, John Roberts, Katherine Lachlan, Mahim Jain, Estelle Colin, Melissa Rumple, Solveig Heide, Kay Metcalfe, Alban Ziegler, Hayley P. Lazar, Elizabeth T. DeChene, Cara M. Skraban, Michael Wright, Karin Weiss, Danielle Monteil, Tamar Paperna, Avni Santani, Hagit Baris Feldman, Bryan L. Krock, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Clinical Genetics, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, 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), Kennedy Krieger Institute [Baltimore], Department of Pediatrics, The University of Texas at San Antonio (UTSA), Universiteit Leiden [Leiden], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Children’s Hospital of Philadelphia (CHOP ), Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, University of Manchester [Manchester], Central Manchester University Hospitals NHS Foundation Trust, Waseda University, CHU Sainte Justine [Montréal], Cancer Genetics Branch, National Institute of Health (NIH)-National Human Genome Research Institute (NHGRI), and Southampton General Hospital
- Subjects
0301 basic medicine ,Male ,[SDV]Life Sciences [q-bio] ,Developmental Disabilities ,030105 genetics & heredity ,chromatin remodeling ,12p13 ,Neurodevelopmental disorder ,Intellectual disability ,Missense mutation ,Global developmental delay ,Child ,Genetics (clinical) ,Genetics ,Syndrome ,Phenotype ,3. Good health ,intellectual disability ,Child, Preschool ,Female ,medicine.symptom ,Mi-2 Nucleosome Remodeling and Deacetylase Complex ,Adult ,Heart Defects, Congenital ,missense ,Adolescent ,Genotype ,Mutation, Missense ,Biology ,Chromatin remodeling ,Article ,12p13.31 ,03 medical and health sciences ,medicine ,Humans ,ATPase ,Abnormalities, Multiple ,Hearing Loss ,Genetic Association Studies ,Macrocephaly ,Infant, Newborn ,Infant ,medicine.disease ,Chromatin Assembly and Disassembly ,Human genetics ,Megalencephaly ,Musculoskeletal Abnormalities ,030104 developmental biology ,Neurodevelopmental Disorders ,Transcription Factors - Abstract
Sifrim–Hitz–Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants in CHD4. In this study, we investigated the clinical spectrum of the disorder, genotype–phenotype correlations, and the effect of different missense variants on CHD4 function. We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype–phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
- Published
- 2020
32. The variability of SMARCA4-related Coffin-Siris syndrome: Do nonsense candidate variants add to milder phenotypes?
- Author
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Janice Baker, Curtis Rogers, Mark Mintz, Maian Roifman, Vikas Bhambhani, Fiona Haslam McKenzie, Julie S. Cohen, Constance Motter, Amy Calhoun, Benjamin Kamien, Alyssa Ritter, Catherine Ward-Melver, Dong Li, Rebecca C. Ahrens-Nicklas, Sharron Townshend, Matthew A. Deardorff, Kirsten M. Niles, Samantha A. Schrier Vergano, Alberto Fernández-Jaén, and Mahim Jain
- Subjects
Hypertrichosis ,Male ,Adolescent ,Chromosomal Proteins, Non-Histone ,media_common.quotation_subject ,Nonsense ,Micrognathism ,Biology ,Genética humana ,Chromatin remodeling ,Intellectual Disability ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,Síndrome de Coffin-lowry ,Child ,Gene ,Coffin–Siris syndrome ,Ciencias médicas ,Genetics (clinical) ,Genetic Association Studies ,media_common ,Coarse facial features ,DNA Helicases ,Infant ,Nuclear Proteins ,medicine.disease ,Phenotype ,DNA-Binding Proteins ,Codon, Nonsense ,Child, Preschool ,Face ,SMARCA4 ,Female ,Hand Deformities, Congenital ,Neck ,Transcription Factors - Abstract
SMARCA4 encodes a central ATPase subunit in the BRG1-/BRM-associated factors (BAF) or polybromo-associated BAF (PBAF) complex in humans, which is responsible in part for chromatin remodeling and transcriptional regulation. Variants in this and other genes encoding BAF/PBAF complexes have been implicated in Coffin–Siris Syndrome, a multiple congenital anomaly syndrome classically characterized by learning and developmental differences, coarse facial features, hypertrichosis, and underdevelopment of the fifth digits/nails of the hands and feet. Individuals with SMARCA4 variants have been previously reported and appear to display a variable phenotype. We describe here a cohort of 15 unrelated individuals with SMARCA4 variants from the Coffin–Siris syndrome/BAF pathway disorders registry who further display variability in severity and degrees of learning impairment and health issues. Within this cohort, we also report two individuals with novel nonsense variants who appear to have a phenotype of milder learning/behavioral differences and no organ-system involvement. Sin financiación 2.802 JCR (2020) Q3, 104/176 Genetics & Heredity 1.064 SJR (2020) Q2, 127/340 Genetics No data IDR 2020 UEM
- Published
- 2020
33. Previously Unidentified Gene Variation Associated with Fabry Disease: The Impact on One Family
- Author
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Thomas R McCune, Amaresh Vanga, Jolanta Kowalewska, and Samantha A. Schrier Vergano
- Subjects
Alanine ,0303 health sciences ,Kidney ,medicine.diagnostic_test ,business.industry ,Genetic disorder ,medicine.disease ,Molecular biology ,Fabry disease ,Diseases of the genitourinary system. Urology ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Nephrology ,Cytoplasm ,Biopsy ,medicine ,Missense mutation ,030212 general & internal medicine ,RC870-923 ,business ,Gene ,030304 developmental biology - Abstract
Fabry disease is an X-linked lysosomal storage genetic disorder associated with over 1000 mutations in the alpha-galactosidase-A gene region. We report here a 69-year-old male who underwent a kidney biopsy to evaluate progressive renal failure. He was found to have zebra bodies in visceral epithelial cells on biopsy, with electron microscopy showing inclusions within the cytoplasm of multiple podocytes consistent with Fabry disease. An alpha-galactosidase level was found to be 21 nm/hr/mg (normal range 50–150 nm/hr/mg). Genetic studies revealed a missense variant in the GLA gene with alanine replaced by cysteine at position 682 (c.682 A > C, p.N228H) that had not been previously associated with Fabry disease. The same variant was detected in two additional family members. The pathologic findings, clinical features, and low alpha-galactosidase level suggest that the c.682 A > C variant is associated with Fabry disease.
- Published
- 2020
34. Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients
- Author
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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
- Subjects
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
- Published
- 2020
35. Consensus Building Using Quality Improvement Tools During the Instructional Design Process
- Author
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Andrew Moore, Gloria Too, Brooke Hooper, Julie A. Bridges, Catherine J. Derber, Kyrie Shomaker, Mily J. Kannarkat, Samantha A. Schrier Vergano, Jessica Burgess, and Bruce Britton
- Subjects
Engineering management ,Quality management ,Instructional design ,Computer science - Abstract
This case outlines the process of using quality improvement tools during the instructional systems design process. The clerkship curriculum of the third year of medical school was undergoing a complete reform in terms of time and content. An instructional designer was utilized to complete a needs analysis and participate in the instructional systems design process. A need for a common understanding of the language of medical education and instructional design drove the team to utilize the Institute for Healthcare Improvement (IHI) Quality Improvement tools. The reform took 11 months, involved six clerkship directors, multiple administrators, and resulted in consensus among the clerkship directors regarding the knowledge, skills, and attitudes appropriate for a third-year medical student curriculum.
- Published
- 2020
36. Schaaf-Yang syndrome overview: Report of 78 individuals
- Author
-
Christian P. Schaaf, Erin Kovar, Daryl A. Scott, John J. McCarthy, Bret L. Bostwick, Yves Lacassie, Joel Charrow, Tony Roscioli, Robert Smiegel, Philip J. Lupo, Megan E. Rech, Katerina Kraft, Edward J. Lose, and Samantha A. Schrier Vergano
- Subjects
Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Genetic counseling ,autism spectrum disorder ,Frameshift mutation ,MAGEL2 ,Young Adult ,03 medical and health sciences ,Neurodevelopmental disorder ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Humans ,Allele ,Child ,Frameshift Mutation ,genotype–phenotype association ,Genetic Association Studies ,Research Articles ,Genetics (clinical) ,neurodevelopment ,business.industry ,Genetic disorder ,Infant ,Proteins ,Syndrome ,Schaaf‐Yang syndrome ,medicine.disease ,Phenotype ,030104 developmental biology ,Codon, Nonsense ,Neurodevelopmental Disorders ,Autism spectrum disorder ,Child, Preschool ,Cohort ,Female ,business ,Research Article - Abstract
Schaaf‐Yang Syndrome (SYS) is a genetic disorder caused by truncating pathogenic variants in the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader‐Willi critical region 15q11‐15q13. SYS is a neurodevelopmental disorder that has clinical overlap with Prader‐Willi Syndrome in the initial stages of life but becomes increasingly distinct throughout childhood and adolescence. Here, we describe the phenotype of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2. This cohort includes 43 individuals that have been reported previously, as well as 35 newly identified individuals with confirmed pathogenic genetic variants. We emphasize that intellectual disability/developmental delay, autism spectrum disorder, neonatal hypotonia, infantile feeding problems, and distal joint contractures are the most consistently shared features of patients with SYS. Our results also indicate that there is a marked prevalence of infantile respiratory distress, gastroesophageal reflux, chronic constipation, skeletal abnormalities, sleep apnea, and temperature instability. While there are many shared features, patients with SYS are characterized by a wide phenotypic spectrum, including a variable degree of intellectual disability, language development, and motor milestones. Our results indicate that the variation in phenotypic severity may depend on the specific location of the truncating mutation, suggestive of a genotype–phenotype association. This evidence may be useful in both prenatal and pediatric genetic counseling.
- Published
- 2018
37. First data from a parent-reported registry of 81 individuals with Coffin-Siris syndrome: Natural history and management recommendations
- Author
-
Hanae Miyawaki, Gijs W. E. Santen, Samantha A. Schrier Vergano, and Elizabeth A. Mannino
- Subjects
Parents ,0301 basic medicine ,Hypertrichosis ,Pediatrics ,medicine.medical_specialty ,Micrognathism ,Cohort Studies ,03 medical and health sciences ,Intellectual Disability ,Intellectual disability ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Registries ,Coffin–Siris syndrome ,Genetic Association Studies ,Genetics (clinical) ,Genetic testing ,medicine.diagnostic_test ,Foot ,Coarse facial features ,business.industry ,Infant ,Aplasia ,Hand ,medicine.disease ,Natural history ,030104 developmental biology ,Child, Preschool ,Face ,Cohort ,business ,Hand Deformities, Congenital ,Neck - Abstract
Coffin-Siris syndrome (CSS; MIM 135900) is a multisystem congenital anomaly syndrome caused by mutations in the genes in the Brg-1 associated factors (BAF) complex. Classically, individuals with CSS have been described with hypo- or aplasia of the fifth digit nails or phalanges (hence the term "fifth digit syndrome"). Other physical features seen include growth restriction, coarse facial features, hypertrichosis or hirsutism, sparse scalp hair, dental anomalies, and other organ-system abnormalities. Varying degrees of developmental and intellectual delay are universal. To date, approximately 200 individuals have been described in the literature. With the advent of large-scale genetic testing such as whole-exome sequencing is becoming more available, more individuals are being found to have mutations in this pathway, and the phenotypic spectrum appears to be broadening. We report here a large cohort of 81 individuals with the diagnosis of CSS from the first parent-reported CSS/BAF complex registry in an effort to describe this variation among individuals, the natural history of the syndrome, and draw some gene-phenotype correlations. We propose that changes in the BAF complex may represent a spectrum of disorders, including both ARID1B-related nonsyndromic intellectual disability (ARID1B-ID) and CSS with classic physical features. In addition, we offer surveillance and management recommendations based on the medical issues encountered in this cohort to help guide physicians and patients' families.
- Published
- 2018
38. Parental Perception and Participation in Genetic Testing Among Children With Autism Spectrum Disorders
- Author
-
Kathryn M. Restaino, Samantha A. Schrier Vergano, Leonard Emuren, and John W. Harrington
- Subjects
Adult ,Male ,Parents ,Autism Spectrum Disorder ,Decision Making ,Primary care ,03 medical and health sciences ,0302 clinical medicine ,Surveys and Questionnaires ,030225 pediatrics ,medicine ,Humans ,Genetic Testing ,Parental perception ,Child ,Aged ,Genetic testing ,medicine.diagnostic_test ,business.industry ,Geneticist ,Middle Aged ,Patient Acceptance of Health Care ,medicine.disease ,Test (assessment) ,Autism spectrum disorder ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Autism ,Female ,business ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
The purpose of this study was to determine the factors associated with genetic testing in children with autism spectrum disorders (ASDs) and understand parental involvement in the decision to test using survey data of parents of children with ASD. Evaluation by a geneticist was associated with genetic testing by more than 39 times compared to evaluation by a nongeneticist (95% CI = 9.15-168.81). Those offered testing by the physicians were more than 6 times more likely to be tested than those not offered testing (95% CI = 1.66-24.61). Financial concerns, not being offered testing, and lack of awareness were the most consistent reasons for not testing given by participants. A physician’s recommendation for testing and an evaluation by a geneticist were the most important factors associated with genetic testing in children with ASD. Educating primary care physicians and nongenetic specialists can potentially improve genetic testing among children with ASD.
- Published
- 2018
39. Congenital methemoglobinemia type II in a 5-year-old boy
- Author
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Jacob M. Wessler, Megan T. Cho, Samantha A. Schrier Vergano, Thomas Pluim, Jane Juusola, and Elizabeth A. Mannino
- Subjects
0301 basic medicine ,leukodystrophy ,Microcephaly ,Pediatrics ,medicine.medical_specialty ,Case Report ,Case Reports ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,medicine ,methemoglobinemia type II ,microcephaly ,Cyanosis ,CYB5R3 ,business.industry ,Leukodystrophy ,methemoglobin reductase ,General Medicine ,medicine.disease ,developmental delay ,030104 developmental biology ,Epilepsy syndromes ,Congenital Methemoglobinemia ,business ,030217 neurology & neurosurgery - Abstract
Key Clinical Message Congenital Methemoglobinemia is a rare neurologic condition which can mimic other diseases such as epilepsy syndromes and leukodystrophies. The responsible gene, CYB5R3, is not typically included on commonly order neurologic and epilepsy panels. We recommend that laboratories include this gene on these tests which often precede larger‐scale genetic studies.
- Published
- 2017
40. Heterozygous variants in PRPF8 are associated with neurodevelopmental disorders
- Author
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LaDonna Immken, David A. Sweetser, François Lecoquierre, Lance H. Rodan, Lauren O’Grady, Emily Bryant, Wendy K. Chung, Nina B. Gold, Dean Sarco, Anne-Marie Guerrot, Samantha A. Schrier Vergano, Roman Yusupov, Laura Schultz-Rogers, Susan Holder, Stephanie Sacharow, Trevor Hoffman, and Sara Cherny
- Subjects
Endocrinology ,Endocrinology, Diabetes and Metabolism ,Genetics ,Molecular Biology ,Biochemistry - Published
- 2021
41. Genotype and phenotype in 12 additional individuals with SATB2 -associated syndrome
- Author
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Berivan Baskin, Holly Dubbs, Marta Szybowska, Cruz Velasco Gonzalez, Jennifer L. Fish, Chumei Li, Yuri A. Zarate, Elaine H. Zackai, Alice Basinger, Richard E. Person, Samantha A. Schrier Vergano, Aisling R. Caffrey, Zhou Luan Xu, Aida Telegrafi, Louisa Kalsner, Julie R. Jones, David B. Everman, and Francisca Millan
- Subjects
0301 basic medicine ,Genetics ,business.industry ,media_common.quotation_subject ,Nonsense ,Phenotype ,Frameshift mutation ,03 medical and health sciences ,030104 developmental biology ,Genotype-phenotype distinction ,Genotype ,Medicine ,Missense mutation ,Craniofacial ,business ,Genetics (clinical) ,Exome sequencing ,media_common - Abstract
SATB2-associated syndrome (SAS) is a multisystemic disorder caused by alterations of the SATB2 gene. We describe the phenotype and genotype of 12 individuals with 10 unique (de novo in 11 of 11 tested) pathogenic variants (1 splice site, 5 frameshift, 3 nonsense, and 2 missense) in SATB2 and review all cases reported in the published literature caused by point alterations thus far. In the cohort here described, developmental delay (DD) with severe speech compromise, facial dysmorphism, and dental anomalies were present in all cases. We also present the third case of tibial bowing in an individual who, just as in the previous 2 individuals in the literature, also had a truncating pathogenic variant of SATB2. We explore early genotype-phenotype correlations and reaffirm the main clinical features of this recognizable syndrome: universal DD with severe speech impediment, mild facial dysmorphism, and high frequency of craniofacial anomalies, behavioral issues, and brain neuroradiographic changes. As the recently proposed surveillance guidelines for individuals with SAS are adopted by providers, further delineation of the frequency and impact of other phenotypic traits will become available. Similarly, as new cases of SAS are identified, further exploration of genotype-phenotype correlations will be possible.
- Published
- 2017
42. Case 3: The Hypothermic Newborn
- Author
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Joshua Erickson and Samantha A. Schrier Vergano
- Subjects
Male ,Resuscitation ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Adenylosuccinate Lyase ,Argininosuccinic Aciduria ,Infant, Newborn ,Emergency department ,Hypothermia ,Hematocrit ,Decreased urine output ,Bolus (medicine) ,Neonatal Screening ,Meconium ,Anesthesia ,Pediatrics, Perinatology and Child Health ,medicine ,Citrulline ,Humans ,medicine.symptom ,business ,Saline - Abstract
A 2-day-old male infant born at 38 weeks to a gravida 1, para 1 woman is brought to the emergency department secondary to concerns for hypothermia, poor feeding, and decreased urine output. Prenatal laboratory results are unremarkable, with the exception of group B Streptococcus colonization that was adequately treated with penicillin prophylaxis before delivery. The delivery course was notable for thick meconium for which the infant underwent intubation and suctioning with subsequent extubation. The infant’s Apgar scores were 4 and 9 at 1 and 5 minutes, respectively. In the nursery, the infant was noted to be breastfeeding well and had passed stools and voided appropriately. He was discharged on day 2 after birth. After discharge, the parents contacted the infant’s physician to report decreased interest in feeding, decreased activity, and low rectal temperature of 93.9°F (34.4°C). The family was instructed to take the infant to the emergency department for further evaluation and treatment. On arrival at the emergency department, the infant was noted to have a temperature of 96.9°F (36.1°C) and to be listless, and was thus taken to a resuscitation bay. Initial physical examination showed an ill-appearing infant with tacky mucous membranes and an exaggerated Moro reflex. He was given a 10-mL/kg normal saline bolus and a 15-mL/kg normal saline bolus. Initial laboratory findings include the following: white blood cells 22,000/μL(22×109/L); hemoglobin 13.3 g/dL (133 g/L); hematocrit 36.5%; platelet count, 565×103/μL (565×109/L); neutrophils 80%; bands 1%; lymphocytes 12%; monocytes 5%; sodium 154 mEq/L (154 mmol/L); potassium 5.1 mEq/L (5.1 mmol/L); chloride 115 mEq/L (115 mmol/L); bicarbonate 20 mEq/L (20 mmol/L); blood …
- Published
- 2019
43. SMARCE1, a rare cause of Coffin-Siris Syndrome: Clinical description of three additional cases
- Author
-
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
44. Characterization of limb differences in children with Cornelia de Lange Syndrome
- Author
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Matthew A. Deardorff, Samantha A. Schrier Vergano, Drew M. Johnson, Sarah E. Noon, Sarika Aggarwal, Devanshi Mehta, Nathan F. Miller, Ian D. Krantz, Laird G. Jackson, Akash Barot, and Maninder Kaur
- Subjects
0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Cornelia de Lange Syndrome ,Genetic counseling ,Limb Deformities, Congenital ,Congenital Abnormalities ,03 medical and health sciences ,Forearm ,De Lange Syndrome ,Genetics ,medicine ,Humans ,Upper Extremity Deformities, Congenital ,Syndactyly ,Child ,Genetics (clinical) ,Retrospective Studies ,business.industry ,NIPBL ,Anatomy ,medicine.disease ,Hypoplasia ,body regions ,Developmental disorder ,030104 developmental biology ,medicine.anatomical_structure ,Mutation ,Etiology ,Cognition Disorders ,business ,Lower Extremity Deformities, Congenital - Abstract
Cornelia de Lange syndrome (CdLS) is a well-described multisystem developmental disorder characterized by dysmorphic facial features, growth and behavioral deficits, and cardiac, gastrointestinal, and limb anomalies. The limb defects seen in CdLS can be mild, with small feet or hands only, or can be severe, with variable deficiency defects involving primarily the ulnar structures and ranging from mild hypoplasia of the fifth digit to complete absence of the forearm. Interestingly, the upper limbs are typically much more involved than the lower extremities that generally manifest with small feet and 2-3 syndactyly of the toes and shortened fourth metatarsal. The upper limbs often manifest asymmetric involvement. The limb findings in our cohort of 378 individuals with CdLS demonstrate a consistent pattern of laterality and symmetry involvement (with increased severity of right-sided limb in individuals with asymmetric limb defects) and a correlation of more significant limb defects with an increased risk of other structural anomalies, and more severe behavioral outcomes. Additionally, we found that individuals with mutations in NIPBL were most likely to have limb defects compared to mutations in other genes with nonsense, exonic deletion, and frameshift mutations being most prevalent in those with limb defects. Characterization of the limb differences in children with CdLS may provide a tool to assist in genetic counseling and determining prognosis. This paper will review the limb involvement in a large cohort of individuals with CdLS assessing the correlation with molecular etiologies, symmetry, additional structural birth defects, and cognitive outcomes. © 2016 Wiley Periodicals, Inc.
- Published
- 2016
45. Case 2: SGA Newborn with Respiratory Distress and Active Precordium
- Author
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Bryan Greenfield, Samantha A. Schrier Vergano, and Alexander R. Ellis
- Subjects
0301 basic medicine ,Respiratory distress ,Respiratory rate ,business.industry ,medicine.medical_treatment ,pCO2 ,03 medical and health sciences ,030104 developmental biology ,Blood pressure ,Fraction of inspired oxygen ,Anesthesia ,Pediatrics, Perinatology and Child Health ,medicine ,Continuous positive airway pressure ,Respiratory system ,business ,Oxygen saturation (medicine) - Abstract
A 2,450-g male newborn is delivered after a full-term gestation by a 35-year-old gravida 2, para 0, aborta 1 woman. The pregnancy was complicated by maternal substance abuse (alcohol, tobacco, and cannabis) as well as intrauterine growth restriction. At delivery, the infant is noted to be dusky, in moderate respiratory distress, and requiring respiratory assistance with continuous positive airway pressure (CPAP). Capillary blood gas is measured on arrival to the NICU, which reveals a pH of 7.22, partial pressure of carbon dioxide (Pco2) of 59 mm Hg (7.9 kPa), partial pressure of oxygen (Po2) of 37 mm Hg (4.9 kPa), and base deficit of –4. On physical examination, his weight is 2.45 kg (less than the 3rd percentile), length is 46.5 cm (10th percentile), and head circumference is 32 cm (3rd percentile.) Vital signs reveal a temperature of 97.7°F (36.5°C); heart rate of 176 beats per minute; respiratory rate of 57 breaths per minute; right leg blood pressure of 61/40 mm Hg, with a mean of 47 mm Hg; and oxygen saturation of 89% while receiving 6 cm H2O CPAP and 30% fraction of inspired oxygen. He is in moderate respiratory distress and appears proportionately small. His anterior fontanel is large and open about 5 to 6 cm in diameter and continuing down into the forehead. His eyes are clear without clouding, nystagmus, or strabismus. He has a normal midface and a somewhat bulbous nasal tip. Ears are normally set. He has a smooth philtrum and a thin upper lip. The palate is intact. He has slight micrognathia. …
- Published
- 2016
46. Correction: The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype–phenotype correlations, and molecular basis
- Author
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Karin Weiss, Hayley P. Lazar, Alina Kurolap, Ariel F. Martinez, Tamar Paperna, Lior Cohen, Marie F. Smeland, Sandra Whalen, Solveig Heide, Boris Keren, Pauline Terhal, Melita Irving, Motoki Takaku, John D. Roberts, Robert M. Petrovich, Samantha A. Schrier Vergano, Amy Kenney, Hanne Hove, Elizabeth DeChene, Shane C. Quinonez, Estelle Colin, Alban Ziegler, Melissa Rumple, Mahim Jain, Danielle Monteil, Elizabeth R. Roeder, Kimberly Nugent, Arie van Haeringen, Michael Gambello, Avni Santani, Līvija Medne, Bryan Krock, Cara M. Skraban, Elaine H. Zackai, Holly A. Dubbs, Thomas Smol, Jamal Ghoumid, Michael J. Parker, Michael Wright, Peter Turnpenny, Jill Clayton-Smith, Kay Metcalfe, Hitoshi Kurumizaka, Bruce D. Gelb, Hagit Baris Feldman, Philippe M. Campeau, Maximilian Muenke, Paul A. Wade, and Katherine Lachlan
- Subjects
Genetics (clinical) - Published
- 2020
47. Congenital lumbar hernia-A feature of diabetic embryopathy?
- Author
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Samantha A. Schrier Vergano, Robert J. Hopkin, Jacob Hogue, Cathy A. Stevens, and Rachel C. Lombardo
- Subjects
musculoskeletal diseases ,0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Hernia ,Maternal diabetes ,030105 genetics & heredity ,Preaxial hallucal polydactyly ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,030225 pediatrics ,Diabetes mellitus ,Diabetic Embryopathy ,Genetics ,medicine ,Humans ,Renal agenesis ,Genetics (clinical) ,Lumbar Vertebrae ,business.industry ,Abdominal wall defect ,Infant, Newborn ,Lumbar hernia ,medicine.disease ,Rib anomalies ,Surgery ,Diabetes, Gestational ,Fetal Diseases ,Child, Preschool ,Female ,business - Abstract
Congenital lumbar hernia is a rare anomaly consisting of protrusion of abdominal organs or extraperitoneal tissue through a defect in the lateral abdominal wall. The majority of affected patients have additional anomalies in a pattern described as the lumbocostovertebral syndrome. We report four patients born to mothers with poorly controlled diabetes with congenital lumbar hernia. All patients exhibited features of lumbocostovertebral syndrome with lumbar hernia, multiple vertebral segmentation anomalies in the lower thoracic and/or upper lumbar spine, rib anomalies, and unilateral renal agenesis. Additional anomalies present in the patients included preaxial hallucal polydactyly, abnormal situs, and sacral dysgenesis, anomalies known to be associated with diabetic embryopathy. At least 11 other patients have been previously reported with the lumbocostovertebral syndrome in the setting of maternal diabetes. We suggest that congenital lumbar hernia and the lumbocostovertebral syndrome are related to diabetic embryopathy.
- Published
- 2018
48. Natural History and Genotype-Phenotype Correlations in 72 Individuals with SATB2-Associated Syndrome
- Author
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Adi Algrabli, Sonal Mahida, William Allen, Cruz Velasco Gonzalez, Marta Szybowska, Aditi Shah Parikh, Quinn Stein, Katie Golden-Grant, David B. Everman, Hailey Pinz, Chumei Li, Mary-Alice Abbott, Anita E. Beck, Alice Basinger, Rebecca McClellan, Victoria Mok Siu, Brittney Knyszek, Leah Fleming, Caroline Brain, Angela Sun, Chantalle Raimondi, Elizabeth A. Sellars, Arti Pandya, Anne Slavotinek, Wendy E. Smith, Meena Balasubramanian, Hazel Perry, Elaine H. Zackai, Michelle Steinraths, E. Martina Bebin, Amelia Kirby, Nathaniel H. Robin, Yuri A. Zarate, Holly Dubbs, Julie Kaylor, Wendy K. Chung, Xilma R. Ortiz-Gonzalez, Margarita Saenz, Louisa Kalsner, Constance Smith-Hicks, Louise C. Wilson, Allison D. Britt, Hilary J. Vernon, Michael J. Gambello, Joseph W. Ray, Katherine A. Bosanko, Carol L. Greene, Samantha A. Schrier Vergano, Julie S. Cohen, Cynthia M. Powell, Jonathan Picker, Alena Egense, Suzanna Schott, Amy R. U. L. Calhoun, Ajith Kuttannair Kumar, Brad Angle, Ali Fatemi, and Hannah Bombei
- Subjects
single nucleotide ,0301 basic medicine ,Male ,Pediatrics ,genetic association studies ,Inheritance Patterns ,polymorphism ,Genotype ,SATB2-associated syndrome ,Medicine ,Young adult ,Child ,Genotype-Phenotype Correlations ,Genetics (clinical) ,Limited speech ,Syndrome ,multiple ,Natural history ,female ,Phenotype ,natural history ,Child, Preschool ,Female ,abnormalities ,SATB ,Adult ,medicine.medical_specialty ,Adolescent ,phenotype ,genotype-phenotype correlation ,Polymorphism, Single Nucleotide ,preschool ,03 medical and health sciences ,Young Adult ,transcription factors ,Genetics ,Humans ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,Craniofacial ,Genetic Association Studies ,business.industry ,Facies ,Infant ,Matrix Attachment Region Binding Proteins ,medicine.disease ,Crowding ,030104 developmental biology ,Macrodontia (tooth) ,facial recognition technology ,business ,Transcription Factors - Abstract
SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.
- Published
- 2018
49. Clinical and molecular spectrum of thymidine kinase 2-related mtDNA maintenance defect
- Author
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Diana Castro, Julia Wang, Honzheng Dai, Vikas Bhambhani, Samantha A. Schrier Vergano, Vikki Stefans, Ayman W. El-Hattab, Fatma Al Jasmi, Catherine Long, Emily Kim, Lee-Jun C. Wong, Hannes Vogel, and Saunder Bernes
- Subjects
Adult ,Male ,Mitochondrial DNA ,Mitochondrial Diseases ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Biology ,Biochemistry ,DNA, Mitochondrial ,Thymidine Kinase ,Young Adult ,Endocrinology ,Muscular Diseases ,Genetics ,Humans ,Child ,Molecular Biology ,Thymidine kinase 2 ,Gene ,Early onset ,Aged ,Infant, Newborn ,Infant ,Middle Aged ,Prognosis ,Phenotype ,Mitochondria ,Child, Preschool ,Mutation ,Female ,Differential diagnosis - Abstract
Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phenotypes that overlap with many other neurological or muscular diseases. Clinicians face the challenge of narrowing down a long list of differential diagnosis when encountered with non-specific neuromuscular symptoms. Biallelic pathogenic variants in the Thymidine Kinase 2 (TK2) gene cause a myopathic form of mitochondrial DNA maintenance defect. Since the first description in 2001, there have been 71 patients reported with 42 unique pathogenic variants. Here we are reporting 11 new cases with 5 novel pathogenic variants. We describe and analyze a total of 82 cases with 47 unique TK2 pathogenic variants in effort to formulate a comprehensive molecular and clinical spectrum of TK2-related mtDNA maintenance disorders.
- Published
- 2018
50. Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care
- Author
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Paola Francesca Ajmone, Maria Luisa Poch-Olive, Jens Erik Klint Nielsen, Christiane Zweier, Giovanni Sorge, Marzia Pollazzon, Bert Callewaert, Jeroen Breckpot, Olivera Djuric, Chiara Baldo, Rikke S. Møller, Isabella Mammi, Livia Garavelli, Gioacchino Scarano, Baris Malbora, Alessandro Iodice, Lucio Giordano, Marina Grasso, Alessandro Pellicciari, Marcella Zollino, Daniele De Brasi, Aurélien Trimouille, Ebtesam M. Abdalla, Samantha A. Schrier Vergano, Ina Schanze, Sébastien Moutton, Anna Kutkowska-Kazmierczak, Agata Fiumara, Andrea Conidi, Emilia Ricci, Duccio Maria Cordelli, Roberta Epifanio, Allan Bayat, Federico Bonvicini, Magdalena Badura-Stronka, Lorenzo Iughetti, Tina Duelund Hjortshøj, Anita Rauch, Vladimir Kuburovic, Giulia Montorsi, Elvis rci Te Valera, Debora Formisano, Stefano Giuseppe Caraffi, Krzysztof Szczaluba, Daniela Santodirocco, Sabine Grønborg, Francesca Faravelli, Maria Antonietta Pisanti, Didier Lacombe, Gijs W. E. Santen, Margherita Silengo, Ivan Ivanovski, Luis G. Tone, Goran Cuturilo, Francesca Mari, Guido Cocchi, Margaret P. Adam, Simonetta Rosato, Chiara Pantaleoni, Patrizia Accorsi, Nicoletta Zanotta, Ewa Obersztyn, Maddalena Baldi, Angelo Selicorni, Alessandra Renieri, Annick Toutain, Mary Beth Dinulos, Petra Muschke, Luigina Spaccini, Luigi Tarani, Igor Prpić, Francesca Rivieri, Koenraad Devriendt, Stefania Bigoni, Robert Smigiel, Anna Luchetti, Federico Raviglione, Martin Zenker, Caterina Lo Rizzo, Salvatore Savasta, Cell biology, and Ivan Ivanovski, Olivera Djuric, Stefano Giuseppe Caraffi, Daniela Santodirocco, Marzia Pollazzon, Simonetta Rosato, Duccio Maria Cordelli, Ebtesam Abballa, Patrizia Accorsi, Margaret P. Adam, Paola Francesca Ajmone, Magdalena Badura-Stronka, Chiara Baldo, Maddalena Baldi, Allan Bayat, Stefania Bigoni, Federico Bonvicini, Jeroen Breckpot, Bert Callewaert, Guido Cocchi, Goran Cuturilo, Daniele De Brasi, Koenraad Devriendt Mary Beth Dinulos, Tina Duelund Hjortshøj, Roberta Epifanio, Francesca Faravelli, Agata Fiumara, Debora Formisano, Lucio Giordano, Marina Grasso, Sabine Grønborg, Alessandro Iodice, Lorenzo Iughetti, Vladimir Kuburovic, Anna Kutkowska-Kazmierczak, Didier Lacombe, Caterina Lo Rizzo, Anna Luchetti, Baris Malbora, Isabella Mammi, Francesca Mari, Giulia Montorsi, Sebastien Moutton, Rikke S. Møller, Petra Muschke, Jens Erik Klint Nielsen, Ewa Obersztyn, Chiara Pantaleoni, Alessandro Pellicciari, Maria Antonietta Pisanti, Igor Prpic, Maria Luisa Poch-Olive, Federico Raviglione, Alessandra Renieri, Emilia Ricci, Francesca Rivieri, Gijs W. Santen, Salvatore Savasta, Gioacchino Scarano, Ina Schanze, Angelo Selicorni, Margherita Silengo, Robert Smigiel, Luigina Spaccini, Giovanni Sorge, Krzysztof Szczaluba, Luigi Tarani, Luis Gonzaga Tone, Annick Toutain, Aurelien Trimouille, Elvis Terci Valera, Samantha Schrier Vergano, Nicoletta Zanotta, Martin Zenker, Andrea Conidi, Marcella Zollino, Anita Rauch, Christiane Zweier, Livia Garavelli
- Subjects
0301 basic medicine ,Male ,BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences ,Microcephaly/diagnosis ,Settore MED/03 - GENETICA MEDICA ,Bioinformatics ,Hirschsprung ,intellectual disability ,management ,Mowat–Wilson syndrome ,ZEB2 ,Hirschsprung Disease/diagnosis ,BOX 1B GENE ,Abnormalities, Multiple/genetics ,Genotype ,Intellectual disability ,Medicine and Health Sciences ,Missense mutation ,Mowat-Wilson syndrome ,Family history ,Child ,Genetics (clinical) ,BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti ,Intellectual Disability/diagnosis ,Phenotype ,ZEB2 gene. Mowat-Wilson syndrome, intellectual disability ,3. Good health ,SIBLINGS ,Child, Preschool ,Microcephaly ,Female ,Adult ,Hirschsprung, intellectual disability, management, Mowat–Wilson syndrome, ZEB2 ,Adolescent ,03 medical and health sciences ,Genetic variation ,medicine ,Humans ,Abnormalities, Multiple ,Hirschsprung Disease ,RECURRENCE ,ZFHX1B MUTATIONS ,Genetic Association Studies ,Genetic association ,Zinc Finger E-box Binding Homeobox 2 ,SPECTRUM ,SMAD-INTERACTING PROTEIN-1 ,business.industry ,CLINICAL-FEATURES ,ZEB2 gene. Mowat-Wilson syndrome ,Biology and Life Sciences ,Facies ,Infant ,HIRSCHSPRUNG-DISEASE ,medicine.disease ,Zinc Finger E-box Binding Homeobox 2/genetics ,DELINEATION ,Genetic Association Studies/methods ,030104 developmental biology ,Mutation ,business ,MENTAL-RETARDATION - Abstract
PurposeMowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221. ispartof: Genetics in Medicine vol:20 issue:9 pages:965-975 ispartof: location:United States status: published
- Published
- 2018
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