ClinGen Dosage Sensitivity Curation Page

PAX9

  • Curation Status: Complete

Location Information

Select assembly: (NC_000014.8) (NC_000014.9)
Evidence for haploinsufficiency phenotype
PubMed ID Description
28910570 In 2018, Wong et al. used PCR and direct sequencing on 120 unrelated individuals displaying tooth agenesis to identify potential variants in PAX9 and MSX1. The patients included in the study did not have tooth agenesis as the result of injuries or dental work. Analysis identified 11 individuals with variants in PAX9. 4 individuals had frameshift variants in PAX9. Of these, 1 was de novo, 2 were paternally inherited, and for 1 inheritance was not confirmed through parental testing. 2 individuals had nonsense variants in PAX9; 1 variant was paternally inherited and parental testing was not performed for the other. In the cases where the variants were paternally inherited, the fathers were affected as well. Additionally, 1 individual had a frameshift variant in PAX9 and a missense variant in MSX1 which were both inherited from their affected mother. The authors do not believe that the MSX1 missense variant greatly contributes to the observed phenotype.
11781684 In 2001, Nieminen et al. used PCR and sequencing on a Finnish family with autosomal dominant oligodontia to identify potential variants in PAX9. The family consisted of an affected mother and 2 affected sons. A variant resulting in a truncated protein was identified in each of these individuals.
24028587 In 2013, Mostowska et al. used direct sequencing on a family with syndromic hypodontia to identify potential variants in MSX1, EDA, WNT10A, and PAX9. The authors identified a frameshift variant (c.59delC) in PAX9 resulting in the protein being truncated by 258 amino acids in the proband with syndromic hypodontia. This variant was also present in the proband?s affected father and grandfather and absent in unaffected family members.

Haploinsufficiency phenotype comments:

Tooth agenesis, selective, 3 Additional Articles: PMID: 22058014 In 2011, Zhu et al. used PCR and direct sequencing on 5 unrelated individuals with tooth agenesis to identify potential variants in PAX9. The authors identified variants in PAX9 in 2 patients. 1 patient with a sporadic case of tooth agenesis was found to have a nonsense variant. Another patient with a familial case of tooth agenesis was found to have a single-nucleotide insertion in PAX9. This individual?s father, paternal uncle, and paternal grandfather were affected by hypodontia, but it appears that testing had not been performed on these family members. PMID: 11827258 (found in ClinVar) In 2002, Frazier-Bowers et al. described a frameshift variant resulting in protein truncation in PAX9 at nucleotide 793 in a family that the authors describe as having, "several individuals affected with molar oligodontia that was transmitted as an isolated autosomal-dominant trait." PMID: 26571067 In 2015, Liang et al. used PCR and sequencing on a family with oligodontia in search of variants in PAX9. Analysis identified a variant (c.2T>G) in the initiation codon of PAX9 in the proband and their 8 affected family members. This variant was absent in the proband's unaffected family members. Per the authors, "we suggest that the heterozygous c.2T>G mutation in PAX9 causes severe or complete inhibition of PAX9 translation at one allele and acts by inactivating one protein copy, leading to haplo-insufficiency." Of note, the authors mention that Klein et. al (PMID: 15615874) has also identified a different initiation codon variant (c.1A>G) in another family with non-syndromic oligodontia. PMID: 22581971 (found in ClinVar) In 2012, Boogaard et al. used PCR on 34 patients with isolated hypodontia to identify potential variants in PAX9, WNT10A, MSX1, IRF6, and AXIN2. Analysis identified 3 patients with variants in PAX9, but 1 of these patients also had a nonsense variant in AXIN2, and the other had a variant believed to be pathogenic in MSX1. The inheritance of these PAX9 variants was not addressed. PMID: 12605438 In 2003, Das et al. used PCR on 3 families with hypodontia to search for variants in PAX9. In 1 family, an insertion was identified in a pair of identical twins. This variant was not detected in other unaffected family members. Of note, the pedigree on the family displayed that the mother had hypodontia as well but was deceased and thus did not receive testing. Per the authors, "The inserted sequence results in a shift in reading frame at aa 58, with a stop codon at aa 177, assuming that exons of the mutant PAX9 gene are spliced in a manner similar to that of the wild-type gene." PMID: 10615120 In 2000, Stockton et al. performed genome-wide analysis, direct sequencing, and single-stranded confirmational polymorphism assay on a family with oligodontia to investigate PAX9. The authors identified a frameshift variant in all of the affected individuals as well as 1 individual whose phenotype could not be confirmed. This variant was absent in the unaffected family members. Per the authors, "Our results indicate that the frameshift mutation in PAX, resulting in an alteration in the paired domain of PAX9, is associated with tooth agenesis. The mutation may have its effect in one of several ways: (i) loss of function due to the absence of the DNA-binding domain; (ii) haploinsufficiency secondary to mutant mRNA or protein instability; (iii) gain of function due to creation of a novel protein; or (iv) dominant-negative effect by interference with the product of the normal PAX9 allele." MSX1 was excluded from analysis in this study. PMID: 28155232 Bonczek et al. review many reported variants in PAX9 related to oligodontia.

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