ArticleThe Journal of clinical endocrinology and metabolism2025
Congenital Hyperinsulinism and Novel KDM6A Duplications -Resolving Pathogenicity With Genome and Epigenetic Analyses.
Article in The Journal of clinical endocrinology and metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Large copy number variants are an important cause of congenital hyperinsulinism that should be screened for during routine testing.Frontiers in endocrinology · 2025Article
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19 authors.
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Abstract
contextHyperinsulinemic hypoglycemia (HI) can be the presenting feature of Kabuki syndrome (KS), which is caused by loss-of-function variants in KMT2D or KDM6A. As these genes play a critical role in maintaining methylation status in chromatin, individuals with pathogenic variants have a disease-specific epigenomic profile-an episignature.
objectiveWe evaluated the pathogenicity of 3 novel partial KDM6A duplications identified in 3 individuals presenting with neonatal-onset HI without typical features of KS at the time of genetic testing.
methodsThree different partial KDM6A duplications were identified by routine targeted next-generation sequencing for HI and initially classified as variants of uncertain significance (VUS) as their location, and hence their impact on the gene, was not known. Whole-genome sequencing (WGS) was undertaken to map the breakpoints of the duplications with DNA methylation profiling performed in 2 individuals to investigate the presence of a KS-specific episignature.
resultsWGS confirmed the duplication in proband 1 as pathogenic as it caused a frameshift in the normal copy of the gene leading to a premature termination codon. The duplications identified in probands 2 and 3 did not alter the reading frame, and therefore their significance remained uncertain after WGS. Subsequent DNA methylation profiling identified a KS-specific episignature in proband 2 but not in proband 3.
conclusionOur 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.
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