Congenital Hyperinsulinism and Novel KDM6A Duplications -Resolving Pathogenicity With Genome and Epigenetic Analyses
Authors' conclusion
Our findings confirm a role for KDM6A partial gene duplications in the etiology of KS and highlight the importance of performing in-depth molecular genetic analysis to properly assess the clinical significance of VUS' in the KDM6A gene.
Study context
- Population
- 3 individuals with neonatal-onset hypoglycemia (HI) without typical features of Kabuki syndrome (KS) at genetic testing, carrying novel partial KDM6A duplications
- Participants
- 3 individuals
- Outcome
- Pathogenicity of 3 novel partial KDM6A duplications
Methodological detailswhole-genome sequencing, DNA methylation profiling, Duplications identified by routine targeted next-generation sequencing for HI, initially classified as variants of uncertain significance (VUS)
- Whole-genome sequencing
- DNA methylation profiling
- Duplications identified by routine targeted next-generation sequencing for HI, initially classified as VUS
Main finding
As reported in the abstract
Pathogenicity of partial KDM6A duplications
- Proband 1: Whole-genome sequencing (WGS) confirmed duplication as pathogenic (frameshift in normal copy causing premature termination codon)
- Probands 2 and 3: duplications did not alter reading frame; significance uncertain after WGS
- DNA methylation profiling: KS-specific episignature in proband 2, not in proband 3
Observational data: associations, not effects.
Original publication
Congenital Hyperinsulinism and Novel KDM6A Duplications -Resolving Pathogenicity With Genome and Epigenetic Analyses. J Clin Endocrinol Metab. Published 30 July 2024. doi:10.
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