Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability

Abstract

Intellectual Disability (ID) is a clinically heterogeneous condition that affects 2–3% of population worldwide. In recent years, exome sequencing has been a successful strategy for studies of genetic causes of ID, providing a growing list of both candidate and validated ID genes. In this study, exome sequencing was performed on 28 ID patients in 27 patient‐parent trios with the aim to identify de novo variants (DNVs) in known and novel ID associated genes. We report the identification of 25 DNVs out of which five were classified as pathogenic or likely pathogenic. Among these, a two base pair deletion was identified in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome (Verheij syndrome). Our result adds to the growing evidence that PUF60 is responsible for the majority of the symptoms reported for carriers of a microdeletion across this region. We also report variants in several genes previously not associated with ID, including a de novo missense variant in NAA15. We highlight NAA15 as a novel candidate ID gene based on the vital role of NAA15 in the generation and differentiation of neurons in neonatal brain, the fact that the gene is highly intolerant to loss of function and coding variation, and previously reported DNVs in neurodevelopmental disorders.

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

“…Review Some mutations in the NAA15 gene, encoding the ribosomebinding subunit of NatA, have also been described, with a clinical picture overlapping with NAA10 mutations. NAA15 has been identified in screens for novel intellectual disability-associated genes (Zhao et al, 2018) and for variants associated with autism or developmental disability (Stessman et al, 2017). Comparing 38 cases of 25 different NAA15 variants, including splice site, frameshift, and missense mutations, a clinical picture with considerable heterogeneity but with some central common features could be seen.…”

Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability

“…In this study we aimed to identify pathogenic variants in families that had previously gone through whole exome sequencing (WES) and chromosomal microarray analysis. 1 Six consanguineous families (4 trios and 2 quads) were selected for whole genome sequencing (WGS), where the proband had an ID or developmental delay (DD) diagnosis in combination with dysmorphology/congenital malformations. WGS was performed to 30× coverage with Illumina HiSeqX using standard protocols.…”

Clinical characterization of a PUF60 variant in a patient with Dubowitz‐like syndrome

“…disease, ocular coloboma, renal and spinal anomalies. Patients have been described with either single-site variants or deletions involving the PUF60 gene (Dauber et al, 2013;El Chehadeh et al, 2016;Graziano et al, 2017;Low et al, 2017;Moccia et al, 2018;Santos-Simarro et al, 2017;Zhao et al, 2018). Of those, seven patients were described in the DECIPHER database (Firth et al, 2009) with 8q24.3 microdeletion syndrome or Verheij syndrome (MIM# 615583).…”