ClinGen Dosage Sensitivity Curation Page

TSPAN7

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
12070254 Abidi et al. (2002) provide a follow up report on a family originally reported by Holinski-Feder et al (PMID: 10449641) in which a frameshift mutation segregates with non-syndromic intellectual disability in four males. Two carrier females had normal intelligence.
10655063 Zemni et al. (2000, PMID: 10655063) report a female with intellectual disability and minor autistic features who had an apparently balanced t(X;2)(p11.4;p21.3) that disrupted TSPAN7. RT-PCR barely detected any transcripts. The authors also report a family with four males with non-syndromic intellectual disability and a nonsense mutation. This mutation is near the 3' end of the gene and RT-PCR showed normal transcription levels. The resulting protein lacks the fourth transmembrane segment and the carboxy-terminal domain. Additional clinical details on this family are provided in De Vos et al, PMID:12150222. Additionally, a missense mutation (P172H) was found in another family with X-linked intellectual disability. This family is further described by Gomot et al., PMID: 12376945. We are not counting the nonsense mutation as evidence from this report due to the normal transcription levels. We did not count the translocation since they did not map the breakpoint on chromosome 2 to show that there is no gene involved from that breakpoint.
26350204 Grozeva et al (2015) performed targeted NGS of 565 intellectual disability (ID)-associated genes on individuals with ID. Multiple TSPAN7 variants were identified, including missense changes and one frameshift. The frameshift change occurred in exon 2 of 8 (NM_004615) and was identified in a male.

Haploinsufficiency phenotype comments:

Two additional patients have been reported with the P172H mutation first described by Zemni et al. Piton et al. (2011) found this mutation in a male with autism and his unaffected mother (PMID: 20479760). Maranduba et al. (2004) reported this mutation in a male with intellectual disability, dysmorphic features, nystagmus, and myopia. It was found in his normal sister and mother but not in his normal brother (PMID: 14735593). Functional studies have not been reported in any of the individuals with this mutation. Partial duplications involving exons 2-8 have been reported in male patients with intellectual disability and/or autism, and their unaffected mothers, PMIDs: 22511893,19339915. However, a similar duplication is listed in DGV as a variant because it was found in controls (PMID:17638019). Furthermore, Cai et al. (2008, PMID:18925931) reported finding a similar duplication a girl with broad spectrum autistic features, her normal sister and mother, but not in her autistic brother. In another family in this paper, a similar duplication was found in a brother and sister with autism, as well as their healthy mother. This group also found the duplication in 2 male and 4 female ethnicity-matched controls and concluded that it was not likely to be pathogenic.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

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

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.