Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported.
We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review.
We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype– phenotype correlations show that late-truncating pathogenic variants (exons 16–17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction.
Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.
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The authors would like to acknowledge the KAT6A Foundation (http://www.kat6a.org/) and all the patients and their families who completed the survey and consented to this study. We would also like to acknowledge the DDD study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee (REC) approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research (NIHR), through the Comprehensive Clinical Research Network. This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome Trust. J.K. held an NIHR Academic Clinical Fellowship post during this course of this study. This work was also supported by an NIH Early Independence Award to V.A.A. (DP5OD024579), and the KAT6A Foundation.
The authors declare no conflicts of interest.