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Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Sarah E SheppardIan M CampbellMargaret H HarrNina B GoldDong LiHans T BjornssonJulie S CohenJill A FahrnerAli FatemiJacqueline R HarrisCatherine NowakCathy A StevensKatheryn GrandMargaret G AuJohn M GrahamPedro A Sanchez-LaraMiguel Del CampoMarilyn C JonesOmar A Abdul-RahmanFowzan Sami AlkurayaJennifer A BassettiKatherine L BergstromElizabeth Joyce BhojSarah DuganJulie D KaplanNada DerarKaren W GrippNatalie S HauserA Micheil InnesBeth KeenaNeslida KodraRebecca MillerBeverly NelsonMalgorzata J NowaczykZuhair RahbeeniShay Ben-ShacharJoseph T ShiehAnne SlavotinekAndrew K SoberingMary-Alice AbbottDawn C AllainLouise Amlie-WolfPing Yee Billie AuEmma C BedoukianGeoffrey BeekJames BarryJanet BergJonathan A BernsteinCheryl CytrynbaumBrian Hon-Yin ChungSarah DonoghueNaghmeh DorraniAlison J EatonJosue A Flores-DaboubHolly DubbsCarolyn A FelixChin-To FongJasmine Lee Fong FungBalram GangaramAmy GoldsteinRotem GreenbergThoa K HaJoseph HershKosuke IzumiStaci KallishElijah KravetsPui-Yan KwokRebekah K JoblingAmy E Knight JohnsonJessica KushnerBo Hoon LeeBrooke LevinKristin LindstromKandamurugu ManickamRebecca MardachElizabeth McCormickD Ross McLeodFrank D MentchKelly MinksColleen MurareskuStanley F NelsonPatrizia PorazziPavel N PichurinNina N Powell-HamiltonZoe PowisAlyssa L RitterCaleb RogersLuis RohenaCarey RonspiesAudrey SchroederZornitza StarkLois Janelle StarrJoan StolerPim SuwannaratMilen VelinovRosanna WeksbergYael WilnaiNeda ZadehDina J ZandMarni J FalkHakon H HakonarsonElaine H ZackaiFabiola Quintero-Rivera
Published in: American journal of medical genetics. Part A (2021)
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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