Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome
Authors: Sheppard Sarah E. , Campbell Ian M. , Harr Margaret H. , Gold Nina , Li Dong , Bjornsson Hans T. , Cohen Julie S. , Fahrner Jill A. , Fatemi Ali , Harris Jacqueline R. , Nowak Catherine , Stevens Cathy A. , Grand Katheryn , Au Margaret , Graham John M. , Sanchez‐Lara Pedro A. , Campo Miguel Del , Jones Marilyn C. , Abdul‐Rahman Omar , Alkuraya Fowzan S. , Bassetti Jennifer A. , Bergstrom Katherine , Bhoj Elizabeth , Dugan Sarah , Kaplan Julie D. , Derar Nada , Gripp Karen W. , Hauser Natalie , Innes A. Micheil , Keena Beth , Kodra Neslida , Miller Rebecca , Nelson Beverly , Nowaczyk Malgorzata J. , Rahbeeni Zuhair , Ben‐Shachar Shay , Shieh Joseph T. , Slavotinek Anne , Sobering Andrew K. , Abbott Mary‐Alice , Allain Dawn C. , Amlie‐Wolf Louise , Au Ping Yee Billie , Bedoukian Emma , Beek Geoffrey , Barry James , Berg Janet , Bernstein Jonathan A. , Cytrynbaum Cheryl , Chung Brian Hon‐Yin , Donoghue Sarah , Dorrani Naghmeh , Eaton Alison , Flores‐Daboub Josue A. , Dubbs Holly , Felix Carolyn A. , Fong Chin‐To , Fung Jasmine Lee Fong , Gangaram Balram , Goldstein Amy , Greenberg Rotem , Ha Thoa K. , Hersh Joseph , Izumi Kosuke , Kallish Staci , Kravets Elijah , Kwok Pui‐Yan , Jobling Rebekah K. , Knight Johnson Amy E. , Kushner Jessica , Lee Bo Hoon , Levin Brooke , Lindstrom Kristin , Manickam Kandamurugu , Mardach Rebecca , McCormick Elizabeth , McLeod D. Ross , Mentch Frank D. , Minks Kelly , Muraresku Colleen , Nelson Stanley F. , Porazzi Patrizia , Pichurin Pavel N. , Powell‐Hamilton Nina N. , Powis Zoe , Ritter Alyssa , Rogers Caleb , Rohena Luis , Ronspies Carey , Schroeder Audrey , Stark Zornitza , Starr Lois , Stoler Joan , Suwannarat Pim , Velinov Milen , Weksberg Rosanna , Wilnai Yael , Zadeh Neda , Zand Dina J. , Falk Marni J. , Hakonarson Hakon , Zackai Elaine H. , Quintero‐Rivera Fabiola 
Published: March 2021

AbstractWiedemann‐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.