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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.

SUBMITTER: Cheng H

PROVIDER: S-EPMC5986698 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Cheng Hanyin H Dharmadhikari Avinash V AV Varland Sylvia S Ma Ning N Domingo Deepti D Kleyner Robert R Rope Alan F AF Yoon Margaret M Stray-Pedersen Asbjørg A Posey Jennifer E JE Crews Sarah R SR Eldomery Mohammad K MK Akdemir Zeynep Coban ZC Lewis Andrea M AM Sutton Vernon R VR Rosenfeld Jill A JA Conboy Erin E Agre Katherine K Xia Fan F Walkiewicz Magdalena M Longoni Mauro M High Frances A FA van Slegtenhorst Marjon A MA Mancini Grazia M S GMS Finnila Candice R CR van Haeringen Arie A den Hollander Nicolette N Ruivenkamp Claudia C Naidu Sakkubai S Mahida Sonal S Palmer Elizabeth E EE Murray Lucinda L Lim Derek D Jayakar Parul P Parker Michael J MJ Giusto Stefania S Stracuzzi Emanuela E Romano Corrado C Beighley Jennifer S JS Bernier Raphael A RA Küry Sébastien S Nizon Mathilde M Corbett Mark A MA Shaw Marie M Gardner Alison A Barnett Christopher C Armstrong Ruth R Kassahn Karin S KS Van Dijck Anke A Vandeweyer Geert G Kleefstra Tjitske T Schieving Jolanda J Jongmans Marjolijn J MJ de Vries Bert B A BBA Pfundt Rolph R Kerr Bronwyn B Rojas Samantha K SK Boycott Kym M KM Person Richard R Willaert Rebecca R Eichler Evan E EE Kooy R Frank RF Yang Yaping Y Wu Joseph C JC Lupski James R JR Arnesen Thomas T Cooper Gregory M GM Chung Wendy K WK Gecz Jozef J Stessman Holly A F HAF Meng Linyan L Lyon Gholson J GJ

American journal of human genetics 20180412 5

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 ...[more]

PMID: 29656860

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Project description:Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well understood. In this population-based cohort study, we examined the familial risk and heritability of ASD with and without co-occurring intellectual disability (ID). We estimated odds ratios and heritability of ASD with ID (ASD+ID) and ASD without ID (ASD-ID) using register-based diagnosis data of 567,436 index persons born in 1984-2009 in Stockholm County, Sweden, and their parents, siblings, cousins, aunts, and uncles. The familial risk profile exhibited differences between ASD-ID and ASD+ID, most notably for index persons with affected parents. For example, for an index person who had at least one parent with ASD, the child's odds of ASD-ID and ASD+ID (95% confidence interval (CI)) increased by 16.2 (14.2-18.6) and 7.4 (5.5-10.0) folds, respectively. The more closely related a family member with ASD was, the greater the observed risk was of ASD in the index person, especially for ASD-ID. The broad-sense heritability (95% CI) for ASD - ID and ASD+ID were 64.6% (46.0-100.0%) and 33.4% (14.4-58.4%), respectively. Familial risk and heritability of ASD may vary by intellectual ability, which implies that risk factors between these ASD phenotypes may differ. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies. LAY SUMMARY: Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well-understood. In a population-based cohort study on families of 567,436 index persons using Swedish registers data, we found that the familial risk profile differed between ASD with and without intellectual disability. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies.

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Dataset Information

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

Publications

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

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