Reverse genotyping: unveiling Alu element insertion as a new cause of Kabuki syndrome using DNA methylation signature

Clin Epigenetics. 2025 Apr 29;17(1):69. doi: 10.1186/s13148-025-01879-z.

Abstract

Kabuki syndrome type 1 (KS1) is a monogenic disorder arising from pathogenic variants within KMT2D and characterized by syndromic neurodevelopmental delay. We report the retrospective identification of a causative AluY insertion within KMT2D in a genetically unsolved individual with typical KS1 features, after identification of a DNA methylation signature. This is the first documentation of Alu insertion as a molecular mechanism responsible for KS1. This study emphasizes the need for reanalyzing inconclusive sequencing data in individuals with gene-specific phenotypes and reinforces episignature as a reliable diagnostic tool when NGS approaches fail to provide conclusive results in individuals with rare diseases.

Keywords: Alu element; KMT2D; Epigenetic signature; Kabuki syndrome; Mobile element insertion.

Publication types

  • Case Reports

MeSH terms

  • Abnormalities, Multiple* / diagnosis
  • Abnormalities, Multiple* / genetics
  • Alu Elements* / genetics
  • DNA Methylation / genetics
  • DNA-Binding Proteins / genetics
  • Face / abnormalities
  • Face / abnormalities
  • Genotyping Techniques / methods
  • Hematologic Diseases* / diagnosis
  • Hematologic Diseases* / genetics
  • Humans
  • Neoplasm Proteins* / genetics
  • Retrospective Studies
  • Vestibular Diseases* / diagnosis
  • Vestibular Diseases* / genetics

Substances

  • DNA-Binding Proteins
  • KMT2D protein, human
  • Neoplasm Proteins

Supplementary concepts

  • Kabuki syndrome