A next-generation episignature for Kabuki syndrome enables fine mapping of the impact of KMT2D variants to inform precision medicine.

KMT2D haploinsufficiency altering DNA methylation

A next-generation DNA methylation episignature for Kabuki syndrome type 1 was generated from the largest cohort to date (110 KMT2D variant carriers, 854 controls) using microarrays and long-read sequencing. The SVM classifier achieved 97% sensitivity and 100% specificity in validation cohorts, outperforming in silico tools. Missense variants in the C-terminal region (exon 48) and N-terminal PHD zinc fingers were predominantly pathogenic for KS1, while central region variants (exons 31–39) were often benign, suggesting potential association with a distinct syndrome. Classifier scores reflected mosaicism levels detected by LRS, and the KS1 episignature positively classified KDM6A (KS2) pathogenic variants.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This next-generation episignature represents a significant advance for KMT2D VUS interpretation, particularly missense variants challenging for conventional tools. Fine mapping by gene region (exon 48 vs central region) opens the door to intra-gene precision medicine. Applicability to long-read platforms strengthens its relevance for future WGS diagnostics.

Clinical impact: 3/3 · Evidence quality: 2/3 · Novelty: 1/2 · Sample size: 1/1 · Journal quality: 1/1 → Total: 8/10