ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: Schizophrenia
Evidence for haploinsufficiency 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).

Haploinsufficiency phenotype comments:

In a followup study to Fromer et al. (2014) Takahashi et al. (2017, PMID: 28159336) Sanger sequenced 464 schizophrenia nuclear families (474 trios comprising 1402 members, including 522 schizophrenics) which was comprised of 60 Chinese, 17 Japanese, and 287 Taiwanese families. The authors sequenced 1401 of their 1402 study participants and did not observe either of the two LoF variants (p.Arg80Ter; p.Lys29AspfsTer10) reported by Fromer et al. (2014) in any of their study participants. Tawamie et al. (2017, PMID: 28257693) identified two independent consanguineous families each with two children affected by autosomal recessive intellectual disability (ID) with microcephaly. Two independent homozygous missense variants in TAF13 were found in each family (family 1: c.119T>A [p.Met40Lys] and family 2: c.92T>A [p.Leu31His]). In both families the homozygous missense variants were found to co-segregate with ID and microcephaly--in family 1 two (of five) children were affected and harbored the homozygous missense variant c.119T>A, in family 2 two (of four) children were affected and harbored the homozygous missense variant c.92T>A. Neither sets of parents were noted to have ID or microcephaly themselves. Through molecular modeling and co-immunoprecipitation assays the authors concluded that these two variants impair the formation of the TAF13-TAF11 heterodimer which is essential for the TAF13-TAF11 heterodimer complex recruitment into the general RNA polymerase II transcription factor IID (TFIID) complex. Furthermore, RNA sequencing of neuroblastoma cell lines with 80% siRNA knock-down of TAF13 revealed deregulation of gene expression patterns with an emphasis on genes related to neuronal and skeletal functions. Neither of these variants are present in ExAC, GnomAD, 1000genomes, or ESP5400. Guo et al. (2018, PMID: 30564305) performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China cohort. A male proband with autism spectrum disorder was identified to harboring a missense variant in exon 3 of the TAF13 gene (NM_005645:c.G110A:p.R37Q). This variant was observed to be maternally inherited. It is unclear if the proband's mother exhibited features of autism spectrum disorder.

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