Growth Impairment and Neurodevelopmental Features in Kabuki Syndrome Type 2: A Case Report With a Novel KDM6A Frameshift Mutation
- 1Animal Biology Department Faculty of Natural Sciences University of Tabriz Tabriz Iran tabrizu.ac.ir
- 2Center of Excellence for Biodiversity Faculty of Natural Sciences University of Tabriz Tabriz Iran tabrizu.ac.ir
- 3Pediatric Health Research Center Mardani Azari Children Hospital Tabriz University of Medical Sciences Tabriz Iran tbzmed.ac.ir
Abstract
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.
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BibTeX
@article{najafzade2026growth,
title = {{Growth Impairment and Neurodevelopmental Features in Kabuki Syndrome Type 2: A Case Report With a Novel KDM6A Frameshift Mutation}},
author = {Sayan Najafzade and Haneieh Honarmand and Mortaza Bonyadi and Mohammad Barzegar},
journal = {Case Reports in Pediatrics},
year = {2026},
month = nov,
doi = {10.1155/crpe/3013437},
url = {https://doi.org/10.1155/crpe/3013437},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Growth Impairment and Neurodevelopmental Features in Kabuki Syndrome Type 2: A Case Report With a Novel KDM6A Frameshift Mutation
AU - Sayan Najafzade
AU - Haneieh Honarmand
AU - Mortaza Bonyadi
AU - Mohammad Barzegar
PY - 2026
DA - 2026/11/04
JO - Case Reports in Pediatrics
DO - 10.1155/crpe/3013437
UR - https://doi.org/10.1155/crpe/3013437
AB - 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.
SN - 2090-6803
SN - 2090-6811
ER -