| Title: |
Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies |
| Authors: |
Cheng, H; Dharmadhikari, AV; Varland, S; Ma, N; Domingo, D; Kleyner, R; Rope, AF; Yoon, M; Stray-Pedersen, A; Posey, JE; Crews, SR; Eldomery, MK; Akdemir, ZC; Lewis, AM; Sutton, VR; Rosenfeld, JA; Conboy, E; Agre, K; Xia, F; Walkiewicz, M; Longoni, M; High, FA; van Slegtenhorst, MA; Mancini, GMS; Finnila, CR; van Haeringen, A; den Hollander, N; Ruivenkamp, C; Naidu, S; Mahida, S; Palmer, EE; Murray, L; Lim, D; Jayakar, P; Parker, MJ; Giusto, S; Stracuzzi, E; Romano, C; Beighley, JS; Bernier, RA; Küry, S; Nizon, M; Corbett, MA; Shaw, M; Gardner, A; Barnett, C; Armstrong, R; Kassahn, KS; Van Dijck, A; Vandeweyer, G; Kleefstra, T; Schieving, J; Jongmans, MJ; de Vries, BBA; Pfundt, R; Kerr, B; Rojas, SK; Boycott, KM; Person, R; Willaert, R; Eichler, EE; Kooy, RF; Yang, Y; Wu, JC; Lupski, JR; Arnesen, T; Cooper, GM; Chung, WK; Gecz, J; Stessman, HAF; Meng, L; Lyon, GJ; Palmer, Elizabeth |
| Source: |
urn:ISSN:0002-9297 ; urn:ISSN:1537-6605 ; American Journal of Human Genetics, 102, 5, 985-994 |
| Publisher Information: |
Elsevier |
| Publication Year: |
2018 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
31 Biological Sciences; 3102 Bioinformatics and Computational Biology; 32 Biomedical and Clinical Sciences; 3105 Genetics; Rare Diseases; Human Genome; Biotechnology; Pediatric Research Initiative; Genetics; Brain Disorders; Intellectual and Developmental Disabilities (IDD); Autism; Congenital Structural Anomalies; Clinical Research; Mental Health; 2.1 Biological and endogenous factors; 1.1 Normal biological development and functioning; Abnormalities; Multiple; Adolescent; Adult; Autism Spectrum Disorder; Cell Line; Child; Exons; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Genetic Variation; Humans |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://hdl.handle.net/1959.4/unsworks_61912; https://doi.org/10.1016/j.ajhg.2018.03.004 |
| DOI: |
10.1016/j.ajhg.2018.03.004 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_61912; https://unsworks.unsw.edu.au/bitstreams/28630ebc-7263-4783-bd7f-0782492d3e58/download; https://doi.org/10.1016/j.ajhg.2018.03.004 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC-BY-NC-ND ; https://creativecommons.org/licenses/by-nc-nd/4.0/ ; free_to_read |
| Accession Number: |
edsbas.9B0963B |
| Database: |
BASE |