Purpose: Mutations in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A mutations has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. Methods: We obtained data for patients with KAT6A mutations through three sources: treating clinicians, an online family survey distributed through social media and a literature review. Results: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic mutations to include missense and splicing mutations. We functionally validated a pathogenic splice site mutation and identified a likely hot-spot location for de novo missense mutations. 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 mutations (exons 16-17) aare significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. Conclusion: Our data expands the genotypic and phenotypic spectrum for individuals with genetic mutations in KAT6A and we outline appropriate clinical management.

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We have expanded the clinical spectrum of autosomal recessive variants by describing a syndrome with features overlapping CS/CISS1 and BOS.