Heterozygous frameshift KMT2A variant in a patient with Wiedemann–Steiner syndrome

Here we report a case of a Japanese girl with Wiedemann–Steiner syndrome carrying a novel heterozygous frameshift variant of KMT2A (NM_001197104.2:c.10123del, p.Thr3375ProfsTer7). Her clinical features included severe pre- and postnatal growth failure, global developmental delay, hypertrichosis and complete agenesis of the corpus callosum. The identified variant truncates the protein, abolishes the C-terminal SET domain required for histone methyltransferase activity, and is predicted to trigger nonsense-mediated mRNA decay, resulting in KMT2A haploinsufficiency—the primary pathogenic mechanism of Wiedemann–Steiner syndrome. This report documents a previously unreported loss-of-function variant in KMT2A with detailed molecular interpretation and phenotypic characterization, contributing to refinement of the mutational spectrum associated with Wiedemann–Steiner syndrome.