ClinGen Dosage Sensitivity Curation Page

TSPAN7

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

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.

Evidence for Triplosenstive Phenotype

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.

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.