CHST3 – Spondyloepiphyseal Dysplasia with Congenital Joint Dislocations

CHST3 encodes chondroitin 6-O-sulfotransferase 1, which catalyzes sulfation of chondroitin sulfate in cartilage. Biallelic CHST3 mutations cause autosomal recessive spondyloepiphyseal dysplasia with congenital joint dislocations (SDCD) characterized by knee, hip, and elbow dislocations at birth, clubfoot, short stature, and progressive kyphoscoliosis. Genetic testing of CHST3 is critical for differential diagnosis among congenital dislocation syndromes.

Clinical Validity

Over 52 probands ([PMID:18513679]; [PMID:20830804]; [PMID:32639237]; [PMID:37183573]) from ≥23 unrelated families ([PMID:20830804]; [PMID:32639237]; [PMID:37183573]), consistent autosomal recessive segregation, and concordant loss-of-function and enzymatic impairment data ([PMID:15215498]; [PMID:19320654]) support a Definitive gene–disease association.

Genetic Evidence

Inheritance is autosomal recessive. Reported variants include eight nonsense/frameshift alleles (e.g., c.83T>A (p.Leu28Ter) [PMID:18513679]), multiple missense substitutions (e.g., c.665G>A (p.Arg222Gln) [PMID:18513679]), small insertions (c.58_77dup (p.Leu26_Phe27insTer) [PMID:18513679]), and recurrent founder alleles c.776T>C (p.Leu259Pro) in Turkish patients ([PMID:32639237]) and c.384_391dup (p.Pro131ArgfsTer88) in Egyptian families ([PMID:37183573]). A total of 24 unique CHST3 mutations have been described across cohorts.

Functional Evidence

Recombinant enzyme assays demonstrate that the p.Arg304Gln mutation abolishes sulfotransferase activity and markedly reduces 6-O-sulfation of chondroitin sulfate chains in patient cells ([PMID:15215498]). The p.Thr141Met substitution reduces C6ST-1 activity to 24–29% of wild type and correlates with severe spinal involvement and cardiac lesions ([PMID:19320654]). Dermal fibroblast studies show decreased 6-O- and compensatory increase in 4-O-sulfation.

Mechanism and Phenotype

Loss of CHST3 activity results in defective proteoglycan sulfation, compromising cartilage matrix integrity and leading to congenital joint instability. Radiographic hallmarks include platyspondyly, flared metaphyses, epiphyseal dysplasia, and kyphoscoliosis developing in late childhood. Extraskel etal features such as clubfoot, rhizomelia, hearing impairment, microdontia, and atrial septal defect may be observed.

Conclusion

Robust genetic and functional data establish CHST3 deficiency as the cause of SDCD. CHST3 sequencing should be offered to patients with congenital large-joint dislocations and characteristic radiographic changes. Early molecular diagnosis enables accurate genetic counseling and anticipatory management of skeletal and cardiac complications.

Key take-home: Biallelic CHST3 variants definitively cause autosomal recessive SDCD and warrant targeted genetic testing for precise diagnosis and management.

References

• American journal of human genetics • 2008 • Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis. PMID:18513679
• American journal of medical genetics. Part A • 2010 • Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features. PMID:20830804
• Clinical dysmorphology • 2020 • Recurrent c.776T>C mutation in CHST3 with four other novel mutations and a literature review. PMID:32639237
• American journal of medical genetics. Part A • 2023 • CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum. PMID:37183573
• Proceedings of the National Academy of Sciences of the United States of America • 2004 • Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. PMID:15215498
• Clinical genetics • 2009 • Omani-type spondyloepiphyseal dysplasia with cardiac involvement caused by a missense mutation in CHST3. PMID:19320654

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