A Novel De Novo Frameshift Mutation in KAT6A Identified by Whole Exome Sequencing

Abstract

Intellectual disability is a common condition with multiple etiologies. The number of monogenic causes has increased steadily in recent years due to the implementation of next generation sequencing. Here, we describe a 2-year-old boy with global developmental delay and intellectual disability. The child had feeding difficulties since birth. He had delayed motor skills and muscular hypotonia. Brain magnetic resonance imaging revealed diffuse white matter loss and thinning of the corpus callosum. Banded karyotype and comparative genomic hybridization (CGH) array were normal. Whole exome sequencing revealed a novel de novo frameshift mutation c.3390delA (p.Lys1130Asnfs*4) in KAT6A gene (NM_006766.4). The heterozygous mutation was confirmed by Sanger sequencing in the patient and its absence in his parents. KAT6A that encodes a histone acetyltransferase has been recently found to be associated with a neurodevelopmental disorder autosomal dominant mental retardation 32 (OMIM: no. 616268). Features of this disorder are nonspecific, which makes it difficult to characterize the condition based on the clinical symptoms alone. Therefore, our findings confirm the utility of whole exome sequencing to quickly and reliably identify the etiology of such conditions.

Keywords: KAT6A; developmental delay; exome; intellectual disability.

Fig. 1

( A ) Family pedigree. The patient symbol is filled black and indicated with an arrow. ( B ) Facial features of the patient at 26 months of age. No major abnormal facial features are present.

Fig. 2

( A ) KAT6A Sanger sequencing traces for the patient (lower) and his parents (upper and middle), showing the single base-pair deletion (c.3390delA) that results in frameshift and consequent truncation of the protein 4 amino acids downstream (p.Lys1130Asnfs*4). Note that the sequence is present in the reverse orientation. ( B ) A schematic illustration of the different domains in the KAT6A protein; NEMM, PHD, HAT, ACIDIC, and SER/MET. The truncated KAT6A forms reported to date (frameshift and nonsense mutations, including our patient's in bold) are shown below. Note that the majority of truncating mutations are within the ACIDIC domain. ACIDIC, acidic glutamate/aspartate-rich domain; HAT, histone acetyltransferase domain; NEMM, nuclear localization domain; PHD, plant zinc finger homeodomain; SER/MET, serine and methionine-rich transactivation domain.