ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
1347148 Tassabehji et al. (1992) identified variations in the PAX3 gene in 6 of 17 unrelated patients with Waardenburg syndrome type 1 (WS1; 193500), using primers to amplify exons 2, 3, 4, followed by testing for heteroduplex formation on polyacrylamide gels. No variants were seen in any exon in 50 normal controls. Amplified mutant alleles from family WS.05 were cloned and sequenced, revealing a heterozygous 18bp deletion in the central region of exon 2, c.185del18, resulting in loss of amino acids 29 to 34 of the paired domain. This variant is segregating for Waardenburg syndrome type 1 in six affected members.
8490648 Following their studies published in previous publication in 1992, Tassabehji et al. (1992), Tassabehji et al. (1993) identified a single base deletion, c.288del1, which truncates the protein product at the start of exon 3 in family WS 06 with 8 affected members. A 2-base deletion in exon 4, c.556delCA, was found segregating for WS1 in family WS11 with 9 affected members.
8533800 Baldwin et al. (1995) described 10 additional mutations in the PAX3 gene in families with WS type 1, including 4 nonsense mutations (p.Q200X, p. S201X, p. E235X, p. Q313X), 3 frameshift mutations (c.874insG, c.954del1, c.1185insTGA), and 3 missense mutations. They also reviewed 2 lof mutations in their previous study in 1994, p.R223X in family BU9 and c. 297del28 in family BU53.

Haploinsufficiency phenotype comments:

Additional literature: PMID:1303193. Morell et al. (1992) identified a 14-bp deletion in the paired domain encoded by exon 2 of the PAX3 in an Indonesian family segregating for Waardenburg syndrome type 1 in 10 affected family members. This frameshift mutation resulted in a premature termination codon in exon 3. The gene product was a truncated protein lacking most of the paired domain and all of the predicted homeodomain. PubMed: 8799378. Wildhardt et al. (1996) described two different PAX3 gene mutations causing Waardenburg syndrome type I . One mutation was frameshift mutation, c.292insT, resulting in a stop codon in exon 3 within the paired domain. The other one was missense mutation, p.Arg271Cys, in the homeobox region. PubMed: 7897628. Hol et al. (1995) identified a 5-bp deletion in exon 5 in a patient with mild sign of WS1. Varying signs of this syndrome were found to cosegregate with the mutation in the family. PubMed: 20478267. Chen et al. (2010) identified a heterozygous 1-bp deletion (556delC) in exon 4 of the PAX3 gene, resulting in a frameshift at premature termination at residue 192 (His186fsTer5) In a Chinese boy with Waardenburg syndrome type 1 PMID: 11683776. Tekin et al. (2001) described a mother and son with typical clinical findings of WS type 3 segregating with a heterozygous 13-bp deletion in the paired domain in exon 3 of the PAX3 gene. Additional literature showed that most of the PAX3 variants found in patients with Waardenburg syndrome type 3 were missense mutations. Therefore, not enough data to establish the haploinsufficiency for Waardenburg syndrome type 3.

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