# 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.

## Key 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.