A next-generation episignature for Kabuki syndrome enables fine mapping of the impact of KMT2D variants to inform precision medicine - PubMed
3 days ago
- #Kabuki syndrome
- #Variant interpretation
- #Episignature
- A next-generation DNA methylation episignature for Kabuki syndrome type 1 (KS1) was developed using a cohort of 110 individuals with KMT2D variants and 854 controls.
- The classifier achieved 97% sensitivity and 100% specificity, outperforming in silico tools and aligning well with clinical presentations.
- Missense variants in the C-terminal region (exon 48) and N-terminal PHD-type zinc fingers of KMT2D were mostly pathogenic, while central region variants (exons 31-39) were often benign, indicating specificity for KS1.
- The episignature performed consistently across microarray and long-read sequencing platforms and reflected mosaicism levels detected by sequencing.
- It also classified pathogenic KDM6A variants associated with KS2, showing broader diagnostic utility for Kabuki syndrome.