Three de novo variants in KMT2A (MLL) identified by whole exome sequencing in patients with Wiedemann–Steiner syndrome. Issue 10 (1st September 2021)

• Record Type: Journal Article
• Authors: Luo, Sukun; Bi, Bo; Zhang, Wenqian; Zhou, Rui; Chen, Wei; Zhao, Peiwei; Huang, Yufeng; Yuan, Li; He, Xuelian
• Is Part Of: Molecular genetics & genomic medicine. Volume 9:Issue 10(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-09-01
• Subjects: de novo variant -- endocardial fibroelastosis -- KMT2A -- neurodevelopment delay -- Wiedemann–Steiner syndrome; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1798
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: Wiedemann–Steiner syndrome (WSS) is an autosomal dominant disorder characterized by short stature, hypertrichosis, intellectual disability, developmental delay, along with facial dysmorphism. WSS patients exhibit great phenotypic heterogeneities. Some variants in KMT2A ( MLL ) gene have been identified as the cause of WSS. Methods: Whole exome sequencing on the probands followed by Sanger sequencing validations in the family were applied to determine genetic variants. In silico analyses were used for predicting potential effects of the variants. Results: We identified three novel de novo heterozygous variants: c.883A>T (p.Lys295*), c.4171C>T (p.Gln1391*), and c.3499T>C (p.Cys1167Arg), in KMT2A gene from three unrelated Chinese WSS patients. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, these three variants were classified as pathogenic, pathogenic and likely pathogenic variant, respectively. By reviewing all the available cases with same mutated KMT2A regions as the three patients had, we found that in addition to the representative symptoms, our patients exhibited some sporadically observed symptoms, such as severe ophthalmological symptoms, endocardial fibroelastosis, cytomegalovirus infection, and feet eversion. We also revealed that variants in different KMT2A regions contribute to the phenotypic heterogeneity of WSS, highlighting challenges in the diagnosis of syndromic disorders spanning a broad phenotypic spectrum. Conclusion: Our study would aid in further broadening our knowledge about the genotype–phenotype correlation of WSS. Abstract : Endocardial fibroelastosis and feet eversion are newly identified features in Wiedemann–Steiner syndrome. Three novel do novo variants identified in this study help to further associate genotype with phenotype in WSS.