PAX8 |
- 1
Haplo
Score - 0
Triplo
Score
Gene Facts External Data Attribution
- HGNC Symbol
- PAX8 (HGNC:8622) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
- HGNC Name
- paired box 8
- Gene type
- protein-coding gene
- Locus type
- gene with protein product
- Previous symbols
- No previous names found
- Alias symbols
- PAX-8
- %HI
- 7.48(Read more about the DECIPHER Haploinsufficiency Index)
- pLI
- 1(Read more about gnomAD pLI score)
- LOEUF
- 0.2(Read more about gnomAD LOEUF score)
- Cytoband
- 2q14.1
- Genomic Coordinates
-
GRCh37/hg19: chr2:113973574-114036498 NCBI Ensembl UCSC GRCh38/hg38: chr2:113215997-113278921 NCBI Ensembl UCSC - MANE Select Transcript
- NM_003466.4 ENST00000429538.8 (Read more about MANE Select)
- Function
- Transcription factor for the thyroid-specific expression of the genes exclusively expressed in the thyroid cell type, maintaining the functional differentiation of such cells. (Source: Uniprot)
Dosage Sensitivity Summary (Gene)
Dosage ID:
ISCA-34702
Curation Status:
Complete
Issue Type:
Dosage Curation -
Gene
Haploinsufficiency:
Little Evidence for Haploinsufficiency
(1)
Triplosensitivity:
No Evidence for Triplosensitivity
(0)
Last Evaluated:
11/09/2021
Haploinsufficiency (HI) Score Details
HI Score:
1
HI Evidence Strength:
Little Evidence for Haploinsufficiency
(Disclaimer)
HI Disease:
- Congenital Hypothyroidism Monarch
HI Evidence:
-
PUBMED:
9590296
Macchia et al. (1998) describe one de novo nonsense variant in the PAX8 gene, as well as two missense variants (1 familial and 1 de novo). The proband with nonsense variant 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 variant led to a lack of DNA binding and reporter transcription.
-
PUBMED:
22898500
Narumi et al. (2012) report on 4 congenital hypothyroidism (CH) associated variants. 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."
-
PUBMED:
33029631
Camats et al (2021) report on 9 PAX8 variants found in 8/93 Catalan pediatric patients detected via neonatal congenital hypothyroidism screening. Eight variants were identified (five novel) including heterozygous (five missense and one indel) and homozygous (one splicing variant). All variants were scored using ACMG criteria. In vitro functional studies of the transactivation activity of the seven variants were undertaken, using a luciferase reporter construct and a wild type/mutant expression vector, which demonstrated impaired activity (51% to 78% of wild type) in five. One of these was attributed to a dominant negative effect on the wild type allele. However all variants were inherited from normal or subclinical parents. In addition, the authors noted that (a) two of this cohort and many published patients have additional variants in other thyroid-related/modifier genes, (b) there were inconsistencies between predicted severity of variant vs phenotype and (c) patients with known variants had different phenotypes to those published previously. They proposed that the pathogenic mechanism of PAX8 is highly variable, with potential genetic and epigenetic modifiers.
-
PUBMED:
15531527
de Sanctis et al. (2004) comprehensively 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 originally screened had congenital hypothyroidism. The mutation was inherited from a well-characterised 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.
-
PUBMED:
26362610
Fu et al. (2015) report an NGS screen of PAX8 in Chinese CH patients: 5 variants were found in 9 patients, including 2 novel nonsense variants that were found to be inherited from unaffected parents.
-
PUBMED:
28444304
de Filippis et al. (2017) undertook a comprehensive characterisation of 11 candidate genes (including PAX8) in 177 unrelated CH patients and 3,538 controls. They showed monogenic, recessive forms of CH in 5 cases, but oligogenic involvement in 39 cases; findings were replicated in an independent cohort of an additional 145 CH cases. Results indicate frequent combinations of rare variants can explain the apparent non-segregation/sporadic occurrences of CH.
HI Evidence Comments:
PAX8 plays dual roles of development and function in the thyroid and has been associated with highly variable congenital hypothyroidism and thyroid dyshormonogenesis phenotypes.
Almost all reported pathogenic variants within PAX8 are missense and nonsense changes. There are no reports of isolated whole gene deletions; a single report from Ma et al, (2014; PMID25484916) describes a patient with a de novo 10.8Mb deletion of 2q13q14.2, however, the deletion contains 38 other OMIM genes including GLI2.
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); one study (PMID: 33029631) demonstrated both mechanisms. Neither the exact mechanism leading to the hypothyroid phenotype nor the variable expressivity and penetrance of this phenotype is understood.
Many identical variants have inconsistent phenotypes between patients, are inherited from normal or subclinical parents, or have variants in other known CH genes. Therefore, we cannot rule out other disease mechanisms, modifier effects and/or environmental factors.
Triplosensitivity (TS) Score Details
TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
Genomic View
Select assembly:
(NC_000002.11)
(NC_000002.12)