PAX3 – Klein-Waardenburg Syndrome (Waardenburg Syndrome Type 3)

PAX3 is a transcription factor critical for neural crest and myogenic development. Heterozygous loss-of-function variants in PAX3 cause Waardenburg syndrome type 1 (WS1) in an autosomal dominant manner, while biallelic variants underlie the more severe Klein-Waardenburg syndrome (WS3) characterized by dystopia canthorum, pigmentary anomalies, and musculoskeletal defects. The association between PAX3 and WS3 is supported by multiple independent homozygous case reports and concordant functional data.

Clinical Validity

Based on three unrelated probands with homozygous PAX3 missense variants presenting with WS3 in consanguineous families, with heterozygous carriers exhibiting only WS1 features, and functional concordance with paired-domain disruption, the gene-disease association is classified as Moderate.

Scores:

• gene_disease_association: Moderate (Three unrelated homozygous probands; heterozygote segregation; functional concordance)

Genetic Evidence

Inheritance: Autosomal recessive.

Segregation: No additional affected homozygotes beyond index cases.

Case reports: Three independent homozygous missense probands in consanguineous kindreds: c.251C>T (p.Ser84Phe) homozygote presenting with WS3 (PMID:7726174), c.268T>C (p.Tyr90His) homozygote in a Turkish child (PMID:12949970), and a third homozygote for c.251C>T (p.Ser84Phe) with severe musculoskeletal involvement (PMID:35607853).

Variant spectrum: Two missense variants in the paired domain; no loss-of-function or splice variants reported in WS3.

genetic_evidence: Moderate (Three homozygous missense probands in AR context; limited segregation data)

Functional / Experimental Evidence

Mechanism: Biallelic disruption of the paired domain impairs DNA binding, causing severe developmental defects. Paired-domain missense mutations (S84F, Y90H) disrupt DNA binding in vitro and in murine splotch models, paralleling the human WS3 phenotype.

functional_evidence: Limited (In vitro DNA-binding assays and murine data confirm pathogenic mechanism for paired-domain variants)

Integration & Clinical Utility

Biallelic PAX3 missense variants in the paired domain cause a distinct AR Klein-Waardenburg syndrome (WS3) phenotype, whereas heterozygotes manifest WS1. Genetic testing for PAX3 should include screening for c.251C>T (p.Ser84Phe) and c.268T>C (p.Tyr90His) in suspected WS3 cases. This distinction informs recurrence risk counseling and management of musculoskeletal anomalies.

Key Take-home: Homozygous PAX3 paired-domain missense variants reliably delineate Klein-Waardenburg syndrome (WS3) and guide AR genetic counseling.

References

• American journal of human genetics • 1995 • Homozygosity for Waardenburg syndrome. PMID:7726174
• American journal of medical genetics. Part A • 2003 • Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome. PMID:12949970
• Clinical genetics • 2022 • Biallelic variants in PAX3 cause Klein syndrome. PMID:35607853

Evidence Based Scoring (AI generated)

Gene–Disease Association Moderate Three unrelated homozygous probands; heterozygote segregation; functional concordance Genetic Evidence Moderate Three homozygous missense probands in AR context; limited segregation data Functional Evidence Limited In vitro DNA-binding assays and murine data confirm mechanism for paired-domain variants