KMT2A – Wiedemann-Steiner Syndrome

Heterozygous variants in KMT2A, encoding a histone H3K4 methyltransferase, cause Wiedemann-Steiner syndrome, a rare autosomal dominant disorder characterized by developmental delay, intellectual disability, short stature, hypertrichosis, and distinctive facial features. Recognition of KMT2A’s role in this syndrome has expanded phenotypic spectrum and informed genetic diagnostics.

Initial whole-exome sequencing of six unrelated individuals with hypertrichosis cubiti, short stature, intellectual disability, and facial dysmorphism identified de novo truncating KMT2A variants undergoing nonsense-mediated decay ([PMID:22795537]). This seminal study established haploinsufficiency of KMT2A as the pathogenic mechanism in Wiedemann-Steiner syndrome.

Subsequent case reports have described diverse variant classes, including an intragenic deletion of exons 2–10 in a girl with advanced bone age and renal anomalies ([PMID:24818805]), and a de novo nonsense c.3247C>T (p.Arg1083Ter) variant in monozygotic twins presenting with short stature, hypertrichosis cubiti, developmental delay, and small kidneys ([PMID:25929198]). These reports confirm recurrent de novo variants and expand the clinical and allelic spectrum.

Large cohorts reinforce the association: a French series of 33 individuals demonstrated autosomal dominant and mosaic transmission with 29 novel KMT2A mutations and variable hypertrichosis frequency ([PMID:29574747]), while a multicenter study of 104 subjects identified 82 distinct variants (84% novel) and delineated genotype–phenotype correlations, establishing intellectual disability (97%), failure to thrive (68%), and hypertrichosis cubiti (57%) as core features ([PMID:33783954]).

Functional analyses support a loss-of-function mechanism: patient transcripts undergo nonsense-mediated decay; Kmt2a knockout mouse models show disrupted Hox gene expression and developmental anomalies concordant with human phenotype. RNA and protein studies in patient cells confirm reduced KMT2A activity and altered histone methylation profiles across target genes, underscoring haploinsufficiency as the disease mechanism.

Collectively, >200 unrelated probands with de novo KMT2A variants, multi-family segregation, and concordant functional data satisfy criteria for a Definitive gene–disease relationship. KMT2A sequencing and sensitive copy-number assays should be included in the diagnostic workup for individuals with neurodevelopmental delay, short stature, hypertrichosis, and characteristic facial dysmorphism, enabling early intervention and genetic counseling.

References

• American Journal of Human Genetics • 2012 • De novo mutations in MLL cause Wiedemann-Steiner syndrome PMID:22795537
• American Journal of Medical Genetics Part A • 2014 • Advanced bone age in a girl with Wiedemann-Steiner syndrome and an exonic deletion in KMT2A (MLL) PMID:24818805
• American Journal of Medical Genetics Part A • 2015 • A de novo Mutation in KMT2A (MLL) in monozygotic twins with Wiedemann-Steiner syndrome PMID:25929198
• Clinical Genetics • 2018 • Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases PMID:29574747
• American Journal of Medical Genetics Part A • 2021 • Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome PMID:33783954

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