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.
| Original language | English |
|---|---|
| Pages (from-to) | 1649-1665 |
| Number of pages | 17 |
| Journal | American Journal of Medical Genetics, Part A |
| Volume | 185 |
| Issue number | 6 |
| Early online date | 30 Mar 2021 |
| DOIs | |
| Publication status | Published - Jun 2021 |
Bibliographical note
Funding text We thank the participants and their families. We also thank the members of the Center for Applied Genomics, CHOP Division of Human Genetics, Roberts Collaborative, and UCLA Clinical Genomics Center. We thank Jessica Douglas MS CGC of Boston Children's Feingold Center and Harvard Undiagnosed Disease Network and Hessa Saad Alsaif of King Faisal Specialist Hospital and Research Centre. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR001880 (S. E. S), and by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania (S. E. S). J. A. F. acknowledges support from Hartwell Foundation, and the NIH (K08HD086250). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The work was partially supported by the University of California, Los Angeles California Center for Rare Diseases. Clinical whole genome sequencing (cWGS) was provided to four patients through the iHope Program. iHope is a philanthropic initiative at Illumina, Inc. in which cWGS is provided to individuals who are suspected of having a genetic etiology to their disease but lack access to this testing. This article reflects the views of the author and should not be construed to represent FDA's views or policies. This work was partially presented at the 40th Annual David W Smith Workshop on Malformations and Morphogenesis, August 23?27, 2019, at the Snowbird Resort in Snowbird, Utah. © 2021 Wiley Periodicals LLC.Other keywords
- Blacks/genetics
- Constipation/epidemiology
- Failure to Thrive/epidemiology
- Genetic Association Studies
- Genetic Predisposition to Disease
- Growth Disorders/epidemiology
- Histone-Lysine N-Methyltransferase/genetics
- Humans
- Hypertrichosis/congenital
- Intellectual Disability/epidemiology
- Loss of Function Mutation/genetics
- Myeloid-Lymphoid Leukemia Protein/genetics
- Retrospective Studies
- Whites/genetics