Growth Impairment and Neurodevelopmental Features in Kabuki Syndrome Type 2: A Case Report With a Novel KDM6A Frameshift Mutation

Kabuki syndrome (KS), a rare epigenetic disorder, arises from pathogenic variants in KMT2D (Kabuki syndrome Type 1 [KS1]; 70%–75% of the cases) or KDM6A (Kabuki syndrome Type 2 [KS2]; 5%–10% of the cases), exhibiting autosomal dominant and X‐linked dominant inheritance patterns, respectively. This study describes a 13‐year‐old girl with classic KS2 manifestations including intellectual disability, ADHD, and short stature (height 130 cm, < 3rd percentile), alongside characteristic dysmorphic features. Her clinical history revealed spontaneous atrial septal defect closure, failure to thrive, and delayed bone age. Whole‐exome sequencing uncovered a novel KDM6A frameshift variant (c.1083_1084delCT), confirmed as de novo , which introduces a premature termination codon in exon 12 (> 50 bp from splice junctions). Computational predictions suggest that the variant likely triggers nonsense‐mediated decay (NMD), resulting in haploinsufficiency. This predicted NMD‐mediated haploinsufficiency is consistent with the established loss‐of‐function disease mechanism of KDM6A‐associated KS2. KDM6A is located on the X chromosome, consistent with the X‐linked classification of this condition. Population studies—including analysis of our cohort of 500 ethnically matched individuals and published data from resources like gnomAD—demonstrate the absence of this variant in healthy populations, further supporting the rarity of the variant (PM2). These findings expand the known mutational spectrum of KS2 and suggest that NMD‐mediated haploinsufficiency may represent a key molecular mechanism. The case highlights the clinical distinctiveness of KS2, particularly its endocrine and growth‐related manifestations, and expands the mutational and phenotypic spectrum of KDM6A‐associated KS2.