CHSY1

Inheritance Pattern: AR

Disease ID:MONDO:0011533

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0011533

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0011533

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0011533

Submitter: ClinGen

The CHSY1 gene was first reported to be causative of autosomal recessive Temtamy preaxial brachydactyly syndrome (TPBS, OMIM #605282) in 2010 (Li et al. 2010. PubMed ID: 21129728; Tian et al. 2010. PubMed ID: 21129727). TPBS is a rare skeletal development disorder characterized by short stature, bilateral, symmetric preaxial brachydactyly and hyperphalangism of digits, facial dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor and mental development, intellectual disability, and macrophthalmia accompanied by bilateral blue sclera in some patients (Temtamy et al. 1998. PubMed ID: 9823490; Race et al. 2010. PubMed ID: 19952732; Li et al. 2010. PubMed ID: 21129728; Tian et al. 2010. PubMed ID: 21129727; Sher and Naeem. 2014. PubMed ID: 24269551). In addition, one missense variant in this gene has been reported in the heterozygous state in a patient with neuropathy which may indicate a dominant negative effect mechanism, however a larger number of patients are needed for further study (Izumikawa et al. 2013. PubMed ID: 23811343). Based on the different phenotype and inheritance pattern, this gene-disease relationship will be assessed separately. The CHSY1 gene is located on chromosome 15q26.3 and encodes chondroitin sulfate synthase 1 (CHSY1), which is a dual glycosyltransferase, transferring glucuronic acid (GlcA) and N-acetyl-galactosamine (GalNAc) residues from UDP-GlcA and UDP-GalNAc, respectively, to the non-reducing end of the elongating chondroitin polymer to form the repeating disaccharide of chondroitin sulfate (CS). CHSY1 is ubiquitously expressed in human tissues and localizes to Golgi apparatus, or secreted. Depletion of CS is observed in a skin section from a patient versus that in control skin (Tian et al. 2010. PubMed ID: 21129727). Moreover, the upregulation of JAG1 and HES1 expression with CHSY1 deficiency were observed. This could be reversed with a wild-type but not a Fringe catalytically dead CHSY1 construct indicating CHSY1 is a secreted FRINGE enzyme required for adjustment of NOTCH signaling throughout human and fish embryogenesis and particularly during limb patterning. In Chsy1-deficient mice, a decrease in 4-O-sulfation and increase in 6-O-sulfation as well as nonsulfated GalNAc residues were detected (Wilson et al. 2012. PubMed ID: 22280990). Furthermore, in embryonic fibroblast cultures from Chsy1-deficient mice, Gli1, the transcriptional target of Hedgehog, is elevated which may indicate that CS and Hedgehog protein may coordinately modulate bone development. To date, 14 variants in CHSY1 (OMIM #608183) including five missense, three nonsense, five deletion, and one splicing variant have been reported or submitted to ClinVar as pathogenic or likely pathogenic as causative for TPBS. This curation includes seven variants (two missense, one nonsense, three deletion, and one splicing variant) in the homozygous state in seven probands from seven consanguineous families in three publications (Li et al. 2010. PubMed ID: 21129728; Tian et al. 2010. PubMed ID: 21129727; Sher and Naeem. 2014. PubMed ID: 24269551). The score for genetic evidence has reached the maximum of 12 pts. The inheritance is autosomal recessive, and the mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence. This includes the non-human animal models of zebrafish and mouse with CHSY1 deficiency, which recapitulate the clinical and histopathological features of the disease in humans (Li et al. 2010. PubMed ID: 21129728; Tian et al. 2010. PubMed ID: 21129727; Wilson et al. 2012. PubMed ID: 22280990; Macke et al. 2020. PubMed ID: 31754016). (Experimental evidence – 4 points). In summary, there is definitive evidence supporting the relationship between CHSY1 and autosomal recessive TPBS/CHSY1-CDG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on June 15, 2026 (SOP Version v12).