Genetic landscape of Kabuki syndrome in Russian patients: spectrum of variants in KMT2D and KDM6A genes

   Introduction. Kabuki syndrome (KS) is a rare hereditary disorder characterized by developmental delay, hypotonia, and a distinctive facial phenotype resembling the makeup of actors in Japanese Kabuki theater. KS is associated with variants in the KMT2D and KDM6A genes, which are critical for histone modification and embryonic development. Despite numerous international studies, the genetic landscape of KS in Russian patients remains unexplored.

   Objective: to identify and characterize the spectrum of molecular causes of KS in a Russian cohort of patients.

   Methods. Next-generation sequencing (NGS) was performed on 37 Russian patients with a clinical diagnosis of KS, including clinical exome sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS).

   Results. Pathogenic or likely pathogenic variants were identified in 22 patients. Seven patients were found to have alternative molecular diagnoses. In KMT2D, 10 frameshift deletions, 4 nonsense variants, 2 in-frame deletions, and 4 missense variants were detected, consistent with global databases. In the KDM6A gene, WES revealed a deletion of exons 3–4, while WGS identified a novel translocation between the X chromosome and chromosome 1 with a breakpoint in intron 28 of KDM6A.

   Conclusions. The results confirm the previously described spectrum of variants in KMT2D and highlight the predisposition of KDM6A to copy number variations (CNVs) and structural variants. This study enhances the understanding of the molecular etiology of KS and underscores the importance of advanced genomic diagnostic methods.

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