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CHSY1 – Temtamy preaxial brachydactyly syndrome

CHSY1 encodes chondroitin sulfate synthase 1, a glycosyltransferase critical for chondroitin sulfate polymerization. Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive disorder characterized by preaxial hyperphalangism, facial dysmorphism, dental anomalies, sensorineural hearing loss, growth delay, and developmental impairment (HP:0000164, HP:0000271, HP:0000407, HP:0001510).

Autosomal recessive inheritance is demonstrated by homozygous variants in two unrelated families. A novel missense variant, c.1897G>A (p.Asp633Asn), segregates in two Pakistani siblings from a consanguineous pedigree (PMID:24269551). An independent truncating frameshift, c.96del (p.Glu33fs), was identified in another TPBS cohort (PMID:21129727). Both variant types co-segregate with disease and are absent in controls.

Segregation analysis supports pathogenicity: the missense allele is homozygous in both affected siblings with obligate carrier parents, and the frameshift segregates recessively in the second family, with no phenotypes in heterozygotes.

Functional studies reveal that patient fibroblasts lack secreted CHSY1 protein and show a loss of chondroitin sulfate synthesis, leading to upregulation of JAG1 and enhanced NOTCH signaling. Complementation with wild-type CHSY1, but not a catalytically dead construct, restores CS chain formation and normalizes NOTCH activity (PMID:21129727).

In vivo, zebrafish chsy1 morpholino knockdown recapitulates skeletal, pectoral-fin, and retinal defects observed in TPBS, and these phenotypes are rescued by human wild-type CHSY1 mRNA but not by the p.Glu33fs variant, confirming loss-of-function as the mechanism.

Overall, two pathogenic alleles in three probands across two families, robust in vitro and in vivo functional concordance, and clear autosomal recessive segregation support a Strong clinical validity classification. CHSY1 testing should be included in diagnostic gene panels for preaxial brachydactyly and syndromic limb malformations.

References

  • European Journal of Medical Genetics • 2014 • A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family. PMID:24269551
  • American Journal of Human Genetics • 2010 • Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling. PMID:21129727

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

Two unrelated families with homozygous missense and truncating variants in CHSY1, consistent autosomal recessive segregation, and concordant functional data in patient cells and animal models [PMID:24269551; PMID:21129727].

Genetic Evidence

Strong

Identification of c.1897G>A (p.Asp633Asn) in two affected siblings from a consanguineous pedigree and independent c.96del (p.Glu33fs) in another family; segregation in extended kindreds supports pathogenicity.

Functional Evidence

Moderate

Patient fibroblasts lack CHSY1 secretion and CS synthesis with NOTCH pathway upregulation; zebrafish knockdown phenocopies the syndrome and is rescued by wild-type but not catalytically dead CHSY1 [PMID:21129727].