Neuronal Heterotopy in a Patient with Wiedemann-Steiner Syndrome Caused by a Truncating KMT2A Variant: Clinical and...

Background and clinical significance: Wiedemann-Steiner syndrome (WSS) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous pathogenic variants in the KMT2A gene, which encodes a histone lysine methyltransferase essential for chromatin regulation. Affected individuals commonly present with developmental delay, intellectual disability, behavioral disturbances, short stature, characteristic facial features, and hypertrichosis, along with variable additional congenital anomalies. Emerging genotype-phenotype correlations suggest two functional classes of KMT2A variants: loss-of-function variants, typically associated with the classic WSS phenotype and muscular hypotonia, and non-loss-of-function variants, which more often correlate with drug-resistant epilepsy and microcephaly. No recurrent variants or clear genotype-phenotype correlations have been established outside the CXXC domain, and most pathogenic variants are private or novel, contributing to phenotypic heterogeneity. Case presentation: We present a case of a 14-year-old female with a pathogenic nonsense truncating variant in the KMT2A gene and typical features of Wiedemann-Steiner syndrome. Additionally, the patient exhibited microcephaly and structural epilepsy due to neuronal heterotopy-features that are rarely described in individuals with truncating variants in this gene and have not been reported in the two published cases of individuals with the same mutation. Conclusions: This case highlights atypical genotype-phenotype correlations and expands the clinical spectrum of truncating KMT2A variants in Wiedemann-Steiner syndrome.