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

TL;DR

A Japanese girl with Wiedemann–Steiner syndrome was found to have a new KMT2A mutation, which helps expand understanding of the genetic causes of this condition.

Contribution

The study reports a novel KMT2A frameshift variant and its molecular and phenotypic implications in Wiedemann–Steiner syndrome.

Findings

The patient exhibited severe growth failure, developmental delay, hypertrichosis, and agenesis of the corpus callosum.

The KMT2A variant truncates the protein and disrupts the SET domain, leading to haploinsufficiency.

The mutation is predicted to trigger nonsense-mediated mRNA decay, supporting its pathogenic role.

Abstract

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.

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