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Sheppard SE, Campbell IM, Harr MH, Gold N, Li D, Bjornsson HT, Cohen JS, Fahrner JA, Fatemi A, Harris JR, Nowak C, Stevens CA, Grand K, Au M, Graham JM, Sanchez-Lara PA, Campo MD, Jones MC, Abdul-Rahman O, Alkuraya FS, Bassetti JA, Bergstrom K, Bhoj E, Dugan S, Kaplan JD, Derar N, Gripp KW, Hauser N, Innes AM, Keena B, Kodra N, Miller R, Nelson B, Nowaczyk MJ, Rahbeeni Z, Ben-Shachar S, Shieh JT, Slavotinek A, Sobering AK, Abbott MA, Allain DC, Amlie-Wolf L, Au PYB, Bedoukian E, Beek G, Barry J, Berg J, Bernstein JA, Cytrynbaum C, Chung BHY, Donoghue S, Dorrani N, Eaton A, Flores-Daboub JA, Dubbs H, Felix CA, Fong CT, Fung JLF, Gangaram B, Goldstein A, Greenberg R, Ha TK, Hersh J, Izumi K, Kallish S, Kravets E, Kwok PY, Jobling RK, Knight Johnson AE, Kushner J, Lee BH, Levin B, Lindstrom K, Manickam K, Mardach R, McCormick E, McLeod DR, Mentch FD, Minks K, Muraresku C, Nelson SF, Porazzi P, Pichurin PN, Powell-Hamilton NN, Powis Z, Ritter A, Rogers C, Rohena L, Ronspies C, Schroeder A, Stark Z, Starr L, Stoler J, Suwannarat P, Velinov M, Weksberg R, Wilnai Y, Zadeh N, Zand DJ, Falk MJ, et alSheppard SE, Campbell IM, Harr MH, Gold N, Li D, Bjornsson HT, Cohen JS, Fahrner JA, Fatemi A, Harris JR, Nowak C, Stevens CA, Grand K, Au M, Graham JM, Sanchez-Lara PA, Campo MD, Jones MC, Abdul-Rahman O, Alkuraya FS, Bassetti JA, Bergstrom K, Bhoj E, Dugan S, Kaplan JD, Derar N, Gripp KW, Hauser N, Innes AM, Keena B, Kodra N, Miller R, Nelson B, Nowaczyk MJ, Rahbeeni Z, Ben-Shachar S, Shieh JT, Slavotinek A, Sobering AK, Abbott MA, Allain DC, Amlie-Wolf L, Au PYB, Bedoukian E, Beek G, Barry J, Berg J, Bernstein JA, Cytrynbaum C, Chung BHY, Donoghue S, Dorrani N, Eaton A, Flores-Daboub JA, Dubbs H, Felix CA, Fong CT, Fung JLF, Gangaram B, Goldstein A, Greenberg R, Ha TK, Hersh J, Izumi K, Kallish S, Kravets E, Kwok PY, Jobling RK, Knight Johnson AE, Kushner J, Lee BH, Levin B, Lindstrom K, Manickam K, Mardach R, McCormick E, McLeod DR, Mentch FD, Minks K, Muraresku C, Nelson SF, Porazzi P, Pichurin PN, Powell-Hamilton NN, Powis Z, Ritter A, Rogers C, Rohena L, Ronspies C, Schroeder A, Stark Z, Starr L, Stoler J, Suwannarat P, Velinov M, Weksberg R, Wilnai Y, Zadeh N, Zand DJ, Falk MJ, Hakonarson H, Zackai EH, Quintero-Rivera F. Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome. Am J Med Genet A 2021; 185:1649-1665. [PMID: 33783954 DOI: 10.1002/ajmg.a.62124] [Show More Authors] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/29/2021] [Accepted: 01/30/2021] [Indexed: 12/19/2022]
Abstract
Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.
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Affiliation(s)
- Sarah E Sheppard
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Ian M Campbell
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Margaret H Harr
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Nina Gold
- Mass General Hospital for Children, Division of Medical Genetics and Metabolism and Harvard Medical School, Boston, Massachusetts, USA
| | - Dong Li
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Hans T Bjornsson
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Faculty of Medicine, University of Iceland, Reykjavik, Iceland.,Landspitali University Hospital, Iceland
| | - Julie S Cohen
- Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, Maryland, USA.,McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jill A Fahrner
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA
| | - Ali Fatemi
- Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, Maryland, USA.,Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jacqueline R Harris
- Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, Maryland, USA.,McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Catherine Nowak
- Division of Genetics and Genomics, Boston Children's Hospital, The Feingold Center for Children, Boston, Massachusetts, USA
| | - Cathy A Stevens
- Department of Pediatrics, University of Tennessee College of Medicine, Chattanooga, Tennessee, USA
| | - Katheryn Grand
- Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, and David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Margaret Au
- Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, and David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - John M Graham
- Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, and David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Pedro A Sanchez-Lara
- Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, and David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, USA
| | - Miguel Del Campo
- Division of Medical Genetics, Department of Pediatrics, University of California, and Rady Children's Hospital, San Diego, California, USA
| | - Marilyn C Jones
- Division of Medical Genetics, Department of Pediatrics, University of California, and Rady Children's Hospital, San Diego, California, USA
| | - Omar Abdul-Rahman
- Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Fowzan S Alkuraya
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Jennifer A Bassetti
- Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA
| | - Katherine Bergstrom
- Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA
| | - Elizabeth Bhoj
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Sarah Dugan
- Division of Medical Genetics, University of Utah, Salt Lake City, Utah, USA
| | - Julie D Kaplan
- Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Nada Derar
- Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Karen W Gripp
- Division of Medical Genetics, Alfred I duPont Hospital for Children, Wilmington, Delaware, USA
| | - Natalie Hauser
- Division of Medical Genomics, Inova Translational Medicine Institute, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - A Micheil Innes
- Department of Medical Genetics, University of Calgary, Calgary, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Beth Keena
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Neslida Kodra
- Division of Medical Genomics, Inova Translational Medicine Institute, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Rebecca Miller
- Division of Medical Genomics, Inova Translational Medicine Institute, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Beverly Nelson
- Department of Clinical Skills, St. George's University, True Blue, Grenada
| | | | - Zuhair Rahbeeni
- Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Shay Ben-Shachar
- Genetic Institute, Tel-Aviv Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Joseph T Shieh
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Anne Slavotinek
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Andrew K Sobering
- Department of Biochemistry, St. George's University, True Blue, Grenada
| | - Mary-Alice Abbott
- Medical Genetics, Department of Pediatrics, University of Massachusetts Medical School - Baystate, Springfield, Massachusetts, USA
| | - Dawn C Allain
- Division of Human Genetics, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Louise Amlie-Wolf
- Division of Medical Genetics, Alfred I duPont Hospital for Children, Wilmington, Delaware, USA
| | - Ping Yee Billie Au
- Department of Medical Genetics, University of Calgary, Calgary, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Emma Bedoukian
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Geoffrey Beek
- Children's Hospital of Minnesota, Minneapolis, Minnesota, USA
| | - James Barry
- Division of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, Texas, USA.,Department of Pediatrics, Long School of Medicine-UT Health San Antonio, San Antonio, Texas, USA
| | - Janet Berg
- Division of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, Texas, USA.,Department of Pediatrics, Long School of Medicine-UT Health San Antonio, San Antonio, Texas, USA
| | - Jonathan A Bernstein
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
| | - Cheryl Cytrynbaum
- Division of Clinical and Metabolic Genetics and Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Brian Hon-Yin Chung
- Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR
| | - Sarah Donoghue
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Naghmeh Dorrani
- Department of Pediatrics, University of California Los Angeles, California, Los Angeles, USA.,UCLA Clinical Genomics Center, University of California Los Angeles, California, Los Angeles, USA
| | - Alison Eaton
- Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
| | | | - Holly Dubbs
- Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Carolyn A Felix
- Division of Oncology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Chin-To Fong
- Department of Pediatrics, Division of Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Jasmine Lee Fong Fung
- Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR
| | - Balram Gangaram
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Amy Goldstein
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Rotem Greenberg
- Genetic Institute, Tel-Aviv Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Thoa K Ha
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Joseph Hersh
- Weisskopf Child Evaluation Center, Department of Pediatrics, University of Louisville, Louisville, Kentucky, USA
| | - Kosuke Izumi
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Staci Kallish
- Division of Translational Medicine and Human Genetics Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Elijah Kravets
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
| | - Pui-Yan Kwok
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Rebekah K Jobling
- Division of Clinical and Metabolic Genetics and Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | | | - Jessica Kushner
- Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA
| | - Bo Hoon Lee
- Department of Neurology, Division of Child Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Brooke Levin
- MD Anderson Cancer Center at Cooper, Cooper University Health Care, Camden, New Jersey, USA
| | | | - Kandamurugu Manickam
- Division of Human Genetics, Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Rebecca Mardach
- Division of Medical Genetics, Department of Pediatrics, University of California, and Rady Children's Hospital, San Diego, California, USA
| | - Elizabeth McCormick
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - D Ross McLeod
- Department of Medical Genetics, University of Calgary, Calgary, Canada
| | - Frank D Mentch
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Kelly Minks
- Department of Neurology, Division of Child Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Colleen Muraresku
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Stanley F Nelson
- UCLA Clinical Genomics Center, University of California Los Angeles, California, Los Angeles, USA.,Department of Human Genetics, Center for Duchenne Muscular Dystrophy University of California Los Angeles, California, Los Angeles, USA
| | - Patrizia Porazzi
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Pavel N Pichurin
- Clinical Genomics Center, University of California Los Angeles, Los Angeles, California, USA
| | - Nina N Powell-Hamilton
- Division of Medical Genetics, Alfred I duPont Hospital for Children, Wilmington, Delaware, USA
| | - Zoe Powis
- Quest Diagnostics Kalamzoo, Kalamzoo, Michigan, USA
| | - Alyssa Ritter
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Caleb Rogers
- Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA
| | - Luis Rohena
- Division of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, Texas, USA.,Department of Pediatrics, Long School of Medicine-UT Health San Antonio, San Antonio, Texas, USA
| | - Carey Ronspies
- Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Audrey Schroeder
- Department of Pediatrics, Division of Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Zornitza Stark
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Australia
| | - Lois Starr
- Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Joan Stoler
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Pim Suwannarat
- Mid-Atlantic Permanente Medical Group, Rockville, Maryland, USA
| | - Milen Velinov
- NYS Institute for Basic Research in developmental Disabilities, Staten Island, New York, USA
| | - Rosanna Weksberg
- Division of Clinical and Metabolic Genetics and Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Yael Wilnai
- Genetic Institute, Sourasky Medical Center, Te-Aviv, Tel Aviv, Israel
| | - Neda Zadeh
- Genetics Center and CHOC Children's Hospital, Orange, California, USA
| | - Dina J Zand
- Rare Disease Institute, Children's National Medical Center, Washington, District of Columbia, USA
| | - Marni J Falk
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Elaine H Zackai
- Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Fabiola Quintero-Rivera
- Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR.,Department of Pathology and Laboratory Medicine, University of California Los Angeles, California, Los Angeles, USA
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