Abstract

Background: Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous pathogenic variants in KMT2A. Although several large international cohorts have helped define its broad clinical spectrum, data from underrepresented populations remain limited.

Aims: To characterize the molecular and phenotypic spectrum of Turkish patients with WDSTS and compare these findings with previously published cohorts.

Study Design: Multicenter retrospective cohort study.

Methods: Sixteen individuals from 15 unrelated families were recruited across Türkiye. Clinical information was obtained through medical records and systematic phenotyping. Molecular analyses included next-generation sequencing or targeted variant testing, and the variants were classified according to the American College of Medical Genetics and Genomics guidelines.

Results: Fifteen distinct KMT2A variants were identified, including nine novel alleles. Most variants were predicted to result in loss of function; only one was a missense substitution. Neurodevelopmental involvement was prominent, with developmental and speech delays, intellectual disability, and behavioral comorbidities such as autism spectrum disorder and attention-deficit/hyperactivity disorder. Endocrine evaluation revealed growth hormone deficiency in approximately half of the tested patients. Ophthalmologic, cardiac, and dental abnormalities, including delayed tooth eruption, further expanded the known phenotype. Additional systemic features included skeletal, genitourinary, and immunological findings. Comparison with previously reported cohorts displayed no statistically significant genotype-phenotype correlations, although truncating variants appeared to be associated with more pronounced neurodevelopmental and behavioral manifestations.

Conclusion: This report presents the largest Turkish WDSTS cohort to date, expands the known KMT2A variant spectrum with nine novel alleles, and highlights several underreported clinical features. Beyond its immediate clinical relevance, the study further supports KMT2A as a key chromatin regulator and an “umbrella gene” within the chromatinopathy spectrum. Growing recognition of these disorders underscores the need for systematic, multidisciplinary surveillance and contributes to the expanding global understanding of their shared pathogenic mechanisms.