ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
24463507 Fromer et al. (2014) performed whole exome sequencing of 623 schizophrenia trios. For each trio the proband had a history of hospitalization for schizophrenia or schizoaffective disorder (study participants were recruited from psychiatric hospitals in Bulgaria). Two unrelated males with schizophrenia (SCZ) harbored de novo sequence variants in TAF13. Proband ID 4080-1 (Supplementary Table 1) harbored a nonsense variant (p.Arg80Ter) while Proband ID 4017-1 (Supplementary Table 1) harbored a frameshift variant (p.Lys29AspfsTer10). Since TAF13 contained two de novo loss of function variants within their study the authors note, "This recurrence is significant even after genome-wide correction (P = 1?10?6; Pcorrected = 0.024)". However, "Replication is necessary to firmly establish this as a susceptibility gene." Neither of these variants were observed in their case-control exome sequencing data set which contains published de novo mutations in unaffected controls and individuals with neuropsychiatric illness. Of note, both variants are present in ExAC (p.Arg80Ter: 1/120768, no homozygotes; p.Lys29AspfsTer10: 1/121278, no homozygotes).

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.