ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000004.11) (NC_000004.12)
Evidence for haploinsufficiency 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. 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. 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.

Haploinsufficiency phenotype comments:

Note: Some of the variants in the above 2 papers were reported in other case control studies for congenital heart defect. Zaidi et. at 2013 (PMID: 23665959) reported 2 de novo ( D335Dfs*6 and S761X, Table S10 ) variants in 2 unrelated patients. fs carrier had normal neurodevelopment, while the NS carrier 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 2 Probands with NAA15 variants was not specified. Homsy et al. 2015 (PMID: 26785492) identified 2 de novo variants ( NS & fs, but no details about the variants) in an exome study of 1213 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 had NDD phenotype (Table S6). In addition, Longoni et al 2017 did WES study of 126 trios enrolled at the Massachusetts General Hospital (MGH) and Boston?s Children Hospital (PubMed: 28303347) and identified a patient with isolated Congenital Diaphragmatic Hernia and a de novo fs variant ( H80fs ). No information about the age and neurodevelopment of this patient, 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. Though there are a considerable number of cases with de novo, putative loss-of-function variants in individuals with neurodevelopmental disorders, there are also individuals with de novo, loss-of-function variants with other phenotypes and without neurodevelopmental disorders (as described above). Given the inconsistency in the phenotype, we are choosing to downgrade the HI score to 2.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity