ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000017.10) (NC_000017.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
12089654 Brown et al. (2002) described two families with phenotypes consistent with stapes ankylosis with broad thumbs and toes (SABTT). In one family, "a heterozygous nonsense mutation?1139C?T, or c.328C?T (Q110X)?was found in all eight affected family members. In the two affected members of [the second family], a 1-bp insertion, 1063-1064insC (c.252-253insC), caused a frameshift that, before encountering a premature stop codon, leads to a mutant peptide with 96 novel amino acids...Neither mutation was found in unaffected family members, spouses, or 100 control samples. In addition, NOG sequencing data from the 100 control samples revealed no variations, as compared to the reference sequence."
16532400 Dawson et al. (2006) reports an individual with a clinical diagnosis of multiple synostoses syndrome (SYNS1) that "was heterozygous for a point mutation (1425G?A) predicted to lead to a premature translation termination codon, W205X (human NOGGIN). This mutation created an Afe1 restriction endonuclease cleavage site, and the mutation was further confirmed by cleavage of a PCR-generated DNA fragment with the enzyme." Inheritance information regarding this variant was not provided, but the individual was reportedly a sporadic case.
11846737 Takahashi et al performed Sanger sequencing of NOG gene is a 3 patients with proximal symphalangism and multiple synostoses syndrome. They identified 1 nonsense variant segregating with phenotype in affected mother and 2 affected sons, and 1 frameshift variant. One de novo missense variant was also identified, but is not counted as evidence toward haploinsufficiency scoring.

Haploinsufficiency phenotype comments:

Additional evidence includes: PMID: 21358557 Thomeer et al. (2011) report two families with proximal symphalangism syndrome and putative loss of function variants in NOG (c.391C>T [p.Gln131X] and c.304del [p.Ala102fs]). Lee et al. (2014) describes a Korean family with multiple synostoses syndrome and a putative loss of function variant in NOG (c.452C>A, p.Ser151Ter). Variants in NOG have been reported in many individuals with various NOG-related Symphalangism Spectrum Disorders, including Brachydactyly type B2, multiple synostoses syndrome (SYNS1), Stapes ankylosis with broad thumb and toes (SABTT), Proximal Symphalangism (SYM1), and Tarsal Carpal Coalition syndrome (TCC). Reported variants include missense, nonsense, and frameshift variants, and particular variants have been associated with more than one of these clinical phenotypes. Precise genotype-phenotype correlations are unclear at this time, though many (not all, however) of the nonsense/truncating variants have been observed in the milder SABTT phenotype. See Potti et al. (2011) for a comprehensive review of NOG variants and phenotypes (PMID:21538686). Though focal deletions of NOG have not been reported at this time, there have been several reports of individuals with larger deletions encompassing NOG with phenotypic features consistent with NOG-related synphalangism spectrum disorders (see Laurell et al. 2013 [PMID:23361222], Shimizu et al. 2008 [PMID:18449926]; Martinez-Fernandez et al. 2015 [PMID:25899082], and others).

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