KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.

Keywords: KAT6A syndrome; chromatin modifiers; intellectual disability; genetic diagnosis; phenotypic spectrum.

Figure 1:. KAT6A domains and the distribution of pathogenic genetic variants.

A) We observed a total of 76 patients with 61 unique genetic variants across the 2004 amino acid protein. The mutations in new patients are shown above the gene, previously reported variants are displayed below the gene. Missense mutations are denoted in red while protein truncating mutations are denoted in black font. Protein ID for KAT6A is NP_006757.2 and various protein domains are: NEMM domain (AA 1-206), PHD domains (AA 207-313), HAT domain(AA 314-787), Acidic domain (788-1414) and Ser/Met domain (1414-2004). B) Splice changes are denoted in blue demonstrating their approximate intronic location in the gene model. C) Missense changes are located near important functional domains of KAT6A described in UniProt. D) The functional effect of the identified splice variant in patient 17 was validated from sequencing of the cDNA product of blood RNA. The splicing effect resulted in a deletion of 8 base pairs and a frameshift change.

Figure 2:

Clinical images of 25 newly reported cases show subtle facial features suggestive of KAT6A syndrome.

Figure 3:. Developmental Delay, Intellectual Disability and Early and Late Truncating Mutations

3a: Developmental milestones in patients with pathogenic mutations in KAT6A. Delay in childhood milestones are commonly seen, with milder delays in social and motor milestones and more severe delay noted in acquisition of verbal language. 3b: Intellectual disability and developmental delay are more severe for truncating mutations in last two exons. A. More severe intellectual disability is more commonly seen in patient with truncating mutations in the last two exons of KAT6A as compared with early truncating mutations (in exons 1-15). Contributing clinicians were asked to rate the level of intellectual disability as mild, moderate or severe on a scale from 1 to 3 (1=mild to 3=severe). Patients collected through the survey or through DDD were asked to report the age when key developmental milestones were reached. We rated the severity of delay for four milestones as mild moderate or severe; first smile (mild=2mth-4mth mod=4-6mths severe=6mths+) Sitting (mild=6-12mths mod=12-18mths severe=18mths+) Walking (mild12-24mth mod=24-30mth severe=30mths+) First word (mild=1-3yrs mod=3-5yr severe=5yr+). The scores for each individual were then averaged to give a score of 1 to 3. 3c: Several syndromic features were seen less commonly in patients with early truncating mutations. This includes microcephaly, neonatal hypotonia, gastrointestinal complications and congenital heart defects.