ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
9590296 Macchia et al. (1998) describe one de novo nonsense mutation in the PAX8 gene, as well as two missense mutations (1 familial and 1 de novo). The proband with nonsense mutation is "heterozygous for a C to T substitution in codon 108 of exon 3," creating a "TGA stop codon, predicting the synthesis of a truncated protein containing only the first 100 amino acids of the paired domain." The proband was diagnosed with congenital hypothyroidism caused by thyroid hypoplasia and ectopy 20 days after birth. The authors showed that this nonsense mutation led to a lack of DNA binding and reporter transcription.
22898500 Narumi et al. (2012) report on 4 congenital hypothyroidism associated mutations. These include 2 inherited missense, 1 de novo missense and 1 inherited frameshift (D46fs). The father and son with the frameshift both have slightly elevated serum TSH levels. The proband has permanent CH and the father has a hypoplastic thyroid. Of note, the father was only evaluated in the context of his son's findings; he was described by the authors as "physically euthyroid." Clinical and molecular data demonstrated that "the D46fs mutation showed abrogated transactivation on the TG promotor irrespective of experimental conditions, supporting that it is actually a null mutation." They report the first experimentally confirmed mutation (D46fs) which causes protein instability, concluding that PAX8 haploinsufficiency is enough to cause CH. The authors also note that the "thyroid phenotypes of the 8 mutation carriers [described in this paper] were considerably variable" and that "chronological changes were observed in several cases."

Haploinsufficiency phenotype comments:

de Sanctis et al. (2004) describe phenotypic variability in a family with a deletion in exon 7 of PAX8 (at codon 277, c.989_992delACCC). This deletion caused a frame shift and the creation of a stop codon directly after the deleted nucleotides. This results in a stable, truncated protein that retained DNA binding ability but no longer activated a reporter. The mutation was not found in 50 healthy controls. The proband that was originally screened has congenital hypothyroidism. The mutation was inherited from a euthyroid mother (normal TSH, fT4, and Tg levels, no anti-thyroid antibodies, normally located and sized thyroid) and also present in a brother with what the authors describe as "compensated hypothyroidism" (elevated TSH and fT4, normal Tg, no anti-thyroid antibodies, normally located and sized thyroid). The brother was described as "asymptomatic," and his elevated TSH levels were only discovered after it was known that he carried the same genetic change as his affected sister (PMID:15531527). Of note, some evidence has also suggested that PAX8 missense mutations can result in congenital hypothyroidism through a dominant negative mechanism (PMIDs: 23308388 and 15718293, also discussed in introduction of PMID: 22898500) while other studies of missense PAX8 mutations seem to lead to haploinsufficiency (PMIDs: 11232006, 15356023, and 11502839). Since neither the exact mechanism leading to the hypothyroid phenotype nor the variable expressivity and penetrance of this phenotype are well understood, a haploinsufficiency score of 2 was selected.

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