NAA15

Gene Facts

• HGNC Symbol: NAA15 (HGNC:30782)
• HGNC Name: N-alpha-acetyltransferase 15, NatA auxiliary subunit
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: NARG1
• Alias symbols: TBDN100, NATH, FLJ13340
• %HI: 7.58
• pLI: 1
• LOEUF: 0.44
• Cytoband: 4q31.1
• Genomic Coordinates:

  GRCh37/hg19:	chr4:140222659-140312538
  GRCh38/hg38:	chr4:139301505-139391384

• MANE Select Transcript: NM_057175.5 ENST00000296543.10
• Function: Auxillary subunit of N-terminal acetyltransferase complexes which display alpha (N-terminal) acetyltransferase (NAT) activity (PubMed:15496142, PubMed:20154145, PubMed:29754825, PubMed:32042062). The NAT activity may be important for vascular, hematopoietic and neuronal growth and development (PubMed:15496142). Required to control retinal neovascularization in adult ocular endothelial cells (PubMed:11687548). In complex with XRCC6 and XRCC5 (Ku80), up-regulates transcription from the osteocalcin... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-24629
• ClinGen Curation ID: CCID:007515
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 04/13/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Syndromic Intellectual Disability

HI Evidence

• PUBMED: 28191889
  Stessman et al. (2017) sequenced 208 candidate genes using single-molecule molecular inversion probes (cover all annotated RefSeq coding exons as well as five base pairs of flanking intronic sequence), from >11,730 patients and >2,867 controls, involving 15 centers across 7 countries and 4 continents. They identified 13 different heterozygous variants (10 are likely gene disruptive including nonsense and frameshift, 3 are missense) in 13 unrelated patients who shared phenotypic features, including intellectual disability (ID) (10/11 patients [91%]), speech delay (5/6 patients [83%]), autism spectrum disorder (ASD) diagnosis (formal diagnosis in 5/8 patients [63%] with ASD-like traits observed in two additional patients), and nonspecific growth abnormalities (e.g., microcephaly, macrocephaly, and hypertelorism). 4 likely gene disruptive variants (2 NS, 2 fs) are demonstrated as de novo. Two MS were inherited without clinical information on parents, and inheritance for the other 7 patients is unknown. De novo likely gene disruptive variants in NAA15 has significant p < 1x10-6. However, functional study was not performed.
• PUBMED: 29656860
  Through WES/WGS and targeted sequencing analysis, Cheng et al. (2018) identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants (13 NS, 2 splicing, 10 fs, Figure 2) in NAA15. The cohort included the patients previously reported by Stessman et al. (2017). Most (22 families) are de novo. Inherited variants in 3 families also segregated with neurocognitive phenotype and showed autosomal dominant inheritance (maternally transmitted to two affected male siblings in family 10, paternally transmitted to an affected male proband in family 22, and maternally transmitted to two affected female siblings in family 28). Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability (23/23), delayed speech (32/33) and motor milestones (31/32), and autism spectrum disorder, ADHD or behavioural issues (30/33) . 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. The author concluded that haploinsufficiency of NAA15 was the most likely mechanism for this variable neurodevelopmental disorder, although the possibility of a dominant-negative or gain-of-function mechanism could not be excluded.
• PUBMED: 28263302
  Yuen et al. 2017 (PMID: 28263302) identified a de novo frameshift variant (c.529_530del (p.T177fs)) in an ASD proband who underwent WGS as part the db4 MSSNG cohort. The db4 MSSNG cohort included 5,205 samples from families with ASD. The clinical description of this proband included eczema, history of "lazy eye" (spontaneously recovered), frequent otitis media, hand flapping, jumping and toe walking, fine motor difficulties, and OCD symptoms. A 3.2 kb deletion of exon 7 of NAA15 was also identified in two affected siblings in this study, and is predicted to be in-frame.

• HI Evidence Comments: Note: There is emerging evidence for an association between loss-of-function variants in NAA15 and congenital anomalies, particularly congenital heart defects. Congenital heart defects (CHD) were present in 4/19 (21%) subjects that were assessed in Cheng et al. 2018 (PMID: 29656860). Some of the variants in Stessman et al. (2017) and Cheng et al. 2018 (2018) were reported in other case control studies for CHD. Zaidi et al. 2013 (PMID: 23665959) reported 2 de novo ( D335Dfs*6 and S761X, Table S10) variants in 2 unrelated patients identified by WES (subjects 1-00141 and 1-00455). Subject 1-00455's neurodevelopmental phenotype was reported inconsistently (see Tables S10 and S11), while subject 1-00141 was not ascertained for that aspect. Age at enrollment for cases is 7.8±9.6 (yro), while 13.7±4.6 (yro) for controls. However, the age of the two Probands with NAA15 variants was not specified. These patients were also published in Homsy et al. 2015 (PMID: 26785492) in a WES study of 1,213 trios recruited in the Pediatric Cardiac Genetics Consortium or the Pediatric Heart Network. Determination of NDD status for both cohorts were evaluated at 12 month, 14 month and 3 yrs of age. Neither patient was reported as having an NDD phenotype in this publication (Table S6). However, subject 1-00455 was later reported in Cheng et al. 2018 as having learning issues, speech issues, hypotonic muscle tone, and being delayed in walking at 2 years of age (Table S2). Ward et al. (ahead of print: https://doi.org/10.1161/CIRCRESAHA.120.316966 ) provided updated phenotypic information for the two subjects previously reported in Zaidi et al. 2013 and Homsy et al. 2015, and identified two additional CHD subjects with LoF variants in NAA15. Three of four LoF variants (p.Ser761*, p.Lys336fs*6, and p.Arg470*) were confirmed de novo by parental testing, and parental samples were unavailable for one patient (p.Ala718fs). In addition to congenital heart defects, all four patients were noted as having neurological phenotypes (Figure 1C, Online Table 1), that included speech disorder (3/4), seizure disorders (3/4), developmental delay (1/4), and behavioural disorders, anxiety and OCD (1/4). In this publication, subject 1-00455 was reported as having speech disorder and subject 1-00141 was reported as having speech disorder and seizure disorder. The authors note that the identification of four NAA15 LoF variants in the 4,511 CHD probands who underwent WES represents a 8.9-fold higher frequency of NAA15 LoF variants in CHD probands compared to the gnomAD population controls (p=0.002). In vitro functional studies performed on iPSC-derived cardiomyocytes confirmed a 50% reduction of full-length NAA15 protein levels in NAA15 +/- cells (with CRISPR derived p.Lys336fs*6 variant), and identified 562 proteins that were differentially expressed in both NAA15+/- and NAA15-/- cardiomyocytes compared to wildtype, including 41 ribosomal-associated proteins. Longoni et al. 2017 (PMID: 28303347) performed a WES study of 126 trios enrolled at the Massachusetts General Hospital (MGH) and Boston’s Children Hospital and identified a patient with isolated Congenital Diaphragmatic Hernia and a de novo fs variant (p.H80fs). No information about the age and neurodevelopment of this patient were provided, but the author did mentioned that all isolated cases (except 5 cases) in this study had no additional anomalies at the time of last contact with a study physician. Ritter et al. 2021 (PMID: 33103328) reported a de novo NAA15 frameshift variant (c.1009_1012delGAAA (p.Glu337fs)) in a 17 month old with paediatric hypertrophic cardiomyopathy (HCM) who presented with cardiac features that included hyperdynamic left ventricle (LC) systolic function, quasi-obliteration of the LC vacity in systole, asymmetric septal hypertrophy and mild-moderate obstructive HCM. No family history of cardiomyopathy, arrhythmias, or NDDs was reported. The patient had global developmental delays, but was too young to be assessed for ID or ASD/ADHD. Mild dysmorphic features and skeletal/connective tissue defects were present, as was bilateral hearing loss. There are a considerable number of cases with de novo, putative loss-of-function variants in individuals with neurodevelopmental disorders. While data from Zaidi et al. 2013 (PMID: 23665959) and Homsy et al. 2015 (PMID: 26785492) initially suggested an association between de novo LoF variants in NAA15 and congenital heart defects without ID/NDDs, updated phenotypic information provided in Cheng et al. (2018) and Ward et al. (https://doi.org/10.1161/CIRCRESAHA.120.316966) supports variable expression of neurological/neurodevelopmental phenotypes in these patients. While the phenotypic spectrum of NAA15 LoF variants remains to be fully characterized, we are choosing to give an HI score of 3 given the large number of cases in the scientific literature, the majority of whom have a reported neurodevelopmental/neurological phenotype.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity