ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
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.
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.
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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.