Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Human Molecular Genetics

Background:

• KAT6A (also known as MOZ) is a histone acetyltransferase involved in transcriptional regulation.
• Previous studies in model organisms (mice, zebrafish) indicated a role for Kat6a in development.
• The specific role of KAT6A in human neurodevelopmental disorders remained largely uncharacterized.

Purpose of the Study:

• To identify the genetic cause of intellectual disability in individuals with overlapping phenotypes.
• To characterize the clinical spectrum associated with KAT6A mutations.
• To establish KAT6A as a causative gene for a distinct intellectual disability syndrome.

Main Methods:

• Whole-exome sequencing (WES) was performed on individuals from five unrelated families.
• Genome-wide array comparative genomic hybridization (aCGH) was used to detect microdeletions.
• Detailed clinical characterization of affected individuals was conducted.

Main Results:

• Five distinct de novo heterozygous truncating mutations in KAT6A were identified via WES.
• One individual had a microdeletion encompassing the entire KAT6A gene identified by aCGH.
• A consistent phenotype was observed, including hypotonia, intellectual disability, feeding difficulties, microcephaly, craniosynostosis, cardiac defects, and specific facial features.

Conclusions:

• Heterozygous mutations in KAT6A cause a distinct intellectual disability syndrome in humans.
• The identified mutations and clinical features provide strong evidence for KAT6A's critical role in human neurodevelopment.
• This study complements findings from animal models, highlighting conserved functions of KAT6A across species.