Genetic analysis of childhood-onset dystonia-28 caused by a variant (c.5076G>A) in the KMT2B gene

Abstract

Objective To investigate the clinical manifestations and genetic basis of childhood-onset dystonia-28 (DYT28) associated with a variant in the KMT2B gene. Methods A female patient, her mother, and her husband, who presented at Zhejiang Provincial People’s Hospital in November 2024, were enrolled in this study. Clinical data were collected, and trio-based whole-exome sequencing (WES) was performed using peripheral blood samples obtained from all three individuals. To further evaluate the effect of the identified variant on RNA splicing, mRNA sequencing (mRNA-seq) and Sanger sequencing were subsequently performed. This study was approved by the Medical Ethics Committee of Zhejiang Provincial People’s Hospital (Approval No. QT2026084). Results The patient presented with gait abnormalities beginning after 10 years of age, accompanied by impaired mathematical ability and language communication difficulties. Her mother exhibited similar clinical manifestations, including gait disturbance, language impairment, and a history of scoliosis. WES identified a heterozygous synonymous variant in exon 23 of the KMT2B gene, c.5076 G>A (p.Lys1692 =), in both the patient and her mother. mRNA-seq analysis demonstrated that the variant produced two aberrantly spliced transcripts: complete skipping of exon 23 and retention of an 18-bp sequence derived from the 5′ end of intron 23. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic based on the following evidence: PVS1_Strong, PP4 and PM2_Supporting. Conclusion The KMT2B c.5076 G>A (p.Lys1692 =) variant is likely the genetic cause of childhood-onset dystonia-28 in this patient. This study expands the mutational spectrum of KMT2B and provides additional evidence to support the genetic diagnosis and counseling of patients with KMT2B-related dystonia.