Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Abstract

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

N-terminal Acetylation Levels Are Maintained During Acetyl-CoA Deficiency in Saccharomyces cerevisiae

“…The herein observed fluctuations in Nt-acetylation may be connected to studies performed in A. thaliana ( 17 ) and C. elegans ( 18 ), in which Nt-acetylation was linked to various stress responses and further supports a role for Nt-acetylation in stress resistance ( 17 , 18 ). Nt-acetylation is implicated in cardiac arrhythmia, developmental delay ( 20 , 78 – 84 ) and cancers ( 85 ). Identifying factors that regulate Nt-acetylation is therefore of great importance.…”

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

“…Patients had neurodevelopmental disabilities, including intellectual disability, autism spectrum disorder, impaired motor function, as well as delayed development. Some had cardiac anomalies and facial dysmorphia (Cheng et al, 2018). Seen in connection with the common feature of intellectual disability or neuromotor impairment in all cases of NAA10 and NAA15 mutation, this suggests that NatA has a crucial function in brain development and, further, that at least some of these phenotypes are caused by impaired NatA function (in contrast to NatA-independent functions of NAA10 and NAA15).…”

Non‐syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies

“…The last XLID update published, estimated that 141 genes are associated with XLID. Since then, more genes have been associated to XLID such as CXorf56 , HS6ST2 , NAA15 , POLA1 and SLC9A7 (Figure ). However, the link of some of these genes to XLID is still questionable .…”