| Category | Details | Key sources (with PMID/DOI when present) |
|---|---|---|
| Disease identifiers | **Temtamy preaxial brachydactyly syndrome (TPBS)**; Mendelian skeletal/limb-malformation syndrome. **MONDO:** MONDO_0011533. **MIM/OMIM phenotype number:** 605282. Open Targets links MONDO_0011533 to **CHSY1** with biallelic loss-of-function evidence and Orphanet/gene2phenotype support. (pqac-00000008, pqac-00000007) | Open Targets MONDO_0011533 (pqac-00000008); Sher 2014, *Eur J Med Genet* DOI: 10.1016/j.ejmg.2013.11.001 (pqac-00000007) |
| Causal gene | **CHSY1** (**chondroitin sulfate synthase 1**), gene MIM **608183**; encodes an ~802-aa enzyme with glycosyltransferase activity involved in **chondroitin sulfate (CS) biosynthesis**. CHSY1 is the single high-confidence associated target in Open Targets for this disease. (pqac-00000005, pqac-00000006, pqac-00000008) | Li 2010, *Am J Hum Genet* DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (pqac-00000005); Tian 2010, *Am J Hum Genet* DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (pqac-00000006) |
| Inheritance | **Autosomal recessive / biallelic** inheritance. Original reports identified affected individuals from **consanguineous families** and mapped the locus by homozygosity/linkage analysis to **15q26-qter**. (pqac-00000004, pqac-00000005, pqac-00000006, pqac-00000008) | Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (pqac-00000004, pqac-00000005); Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (pqac-00000006) |
| Core phenotypes | Hallmark phenotype is **bilateral, symmetric preaxial brachydactyly** with **hyperphalangism** (especially digits 1–3). Common associated findings include **facial dysmorphism**, **dental anomalies**, **sensorineural hearing loss**, **short stature/growth retardation**, and in some reports **developmental delay**. (pqac-00000004, pqac-00000005, pqac-00000006, pqac-00000007, pqac-00000014) | Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (pqac-00000004, pqac-00000005, pqac-00000014); Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (pqac-00000006); Sher 2014 DOI: 10.1016/j.ejmg.2013.11.001 (pqac-00000007) |
| Key radiographic findings | Radiographs show **partial duplication/splitting of proximal phalanges** in preaxial digits, **hyper- and symphalangism**, **radio-ulnar synostosis**, and **carpal/tarsal fusions**; Table/Figure summaries in Li 2010 depict characteristic hand/foot radiographs and mutation positions. (pqac-00000002, pqac-00000004, pqac-00000014) | Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (pqac-00000002); Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (pqac-00000004, pqac-00000014) |
| Representative pathogenic variants: Li 2010 | Reported **CHSY1 loss-of-function** alleles included **c.55_84del30 (p.Gly19_Leu28del)**, **c.14delG (p.Gly5Alafs*29)**, **c.205C>T (p.Gln69*)**, **c.321-3C>G** (splice-site), and **c.1616C>G (p.Pro539Arg)**; variants segregated with disease and were absent in tested controls. (pqac-00000001, pqac-00000004, pqac-00000005, pqac-00000014) | Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (pqac-00000004, pqac-00000005, pqac-00000014); Pawlik 2010 summary (pqac-00000001) |
| Representative pathogenic variants: Tian 2010 | Tian et al. independently identified **truncating frameshift loss-of-function CHSY1 alleles** in an autosomal-recessive syndromic brachydactyly family and linked CHSY1 deficiency to abnormal NOTCH signaling output. (pqac-00000006, pqac-00000002) | Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (pqac-00000006, pqac-00000002) |
| Representative pathogenic variants: Sher 2014 | Sher et al. reported a novel homozygous missense variant **c.1897G>A (p.Asp633Asn / D633N)** in a consanguineous Pakistani family; the paper noted that previously known TPBS variants included both **protein-truncating/deletion** and **missense** alleles. (pqac-00000003, pqac-00000007) | Sher 2014, *Eur J Med Genet* DOI: 10.1016/j.ejmg.2013.11.001 (pqac-00000003, pqac-00000007) |
| Mechanism: glycosaminoglycan biology | CHSY1 is required for **chondroitin sulfate biosynthesis**; TPBS is therefore part of the spectrum of disorders caused by defects in **glycosaminoglycan (GAG) synthesis**. Disrupted CS/proteoglycan production is thought to impair cartilage/bone development and morphogen signaling during limb and craniofacial patterning. (pqac-00000005, pqac-00000006, pqac-00000007) | Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (pqac-00000005); Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (pqac-00000006); Sher 2014 DOI: 10.1016/j.ejmg.2013.11.001 (pqac-00000007) |
| Mechanism: BMP signaling | Li et al. identified CHSY1 as a **potential target of BMP signaling**; in zebrafish, **BMP signaling negatively regulated chsy1 expression**, and perturbation of chsy1 caused developmental defects resembling TPBS. (pqac-00000004, pqac-00000005, pqac-00000001) | Li 2010 DOI: 10.1016/j.ajhg.2010.10.003; PMID: 21129727 (pqac-00000004, pqac-00000005); Pawlik 2010 summary (pqac-00000001) |
| Mechanism: NOTCH signaling | Tian et al. proposed that CHSY1 also acts as a **secreted FRINGE-like regulator**: loss of CHSY1 led to **increased JAG1/JAG2 and subsequent NOTCH activation**, linking extracellular CHSY1 deficiency to abnormal limb patterning. (pqac-00000002, pqac-00000006) | Tian 2010 DOI: 10.1016/j.ajhg.2010.11.005; PMID: 21129728 (pqac-00000002, pqac-00000006) |
| Evidence/implementation notes | Evidence is primarily from **aggregated disease-level rare-disease/genomics resources** plus **small human family studies** and **zebrafish functional work**. No disease-specific interventional clinical trials were identified in the searched clinical-trials results. (pqac-00000008, pqac-00000005, pqac-00000006) | Open Targets disease-target evidence (pqac-00000008); Li 2010 PMID: 21129727 (pqac-00000005); Tian 2010 PMID: 21129728 (pqac-00000006) |


*Table: This table condenses the core identifiers, genetics, phenotype, radiographic findings, representative variants, and mechanisms for Temtamy preaxial brachydactyly syndrome. It is useful as a quick-reference artifact for building a disease knowledge base entry with source-linked evidence.*