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Desbuquois dysplasia (DBQD) is a rare autosomal recessive skeletal disorder characterized by short-limbed dwarfism, joint laxity, advanced carpal ossification, and distinctive facial features (MONDO:0015426). Two clinical subtypes exist: type I, caused by biallelic CANT1 mutations, and type II, attributed to biallelic XYLT1 variants. XYLT1 encodes xylosyltransferase I (XT-I), the initiating enzyme in proteoglycan biosynthesis crucial for cartilage matrix formation.
Genetic evidence for XYLT1 in DBQD type II includes 10 probands from nine unrelated autosomal recessive families: seven subjects from six consanguineous pedigrees (PMID:24581741), two probands from two Turkish families (PMID:27881841), and one singleton case report (PMID:28462984). All patients harbor homozygous or compound heterozygous XYLT1 loss-of-function or catalytic domain missense variants, segregating with disease in consanguineous families.
The variant spectrum comprises frameshift duplications (e.g., c.2169dup (p.Val724SerfsTer10)), splice-site changes, nonsense mutations, and recurrent missense alleles (p.Arg598Cys, p.Arg481Trp) within the catalytic domain. Over 70% of reported alleles are predicted or demonstrated to abolish enzyme function, consistent with autosomal recessive inheritance and absence of disease in heterozygous carriers.
Functional studies demonstrate that XYLT1 pathogenic variants lead to endoplasmic reticulum retention of XT-I and a drastic reduction of cellular proteoglycan content in patient fibroblasts (PMID:28462984; PMID:24581741). In the pug mouse model, a missense Xylt1 allele causes reduced glycosaminoglycan chains, premature chondrocyte maturation, and shortened long bones, faithfully recapitulating the human phenotype (PMID:24161523).
Mechanistically, loss of XT-I activity disrupts the initial step of glycosaminoglycan linker formation, leading to deficient extracellular matrix proteoglycans, aberrant ossification, and skeletal dysplasia. Concordant genetic and experimental data support a loss-of-function haploinsufficiency mechanism under an autosomal recessive model.
No conflicting reports disputing XYLT1’s role in DBQD type II have been documented. The strong genetic segregation, variant recurrence in unrelated populations, and robust functional concordance across cellular and animal models fulfill ClinGen criteria for a Strong gene–disease association.
Key Take-home: Biallelic loss-of-function and catalytic domain missense variants in XYLT1 cause Desbuquois dysplasia type II by impairing XT-I activity and proteoglycan biosynthesis, supporting genetic diagnosis and potential enzyme‐targeted interventions.
Gene–Disease AssociationStrong10 probands from nine unrelated families, segregation in consanguineous pedigrees, concordant functional data Genetic EvidenceStrongMultiple homozygous loss-of-function variants in 10 probands; reached typical genetic evaluation cap Functional EvidenceModerateER retention and reduced proteoglycan content in patient fibroblasts and HeLa cells; mouse model recapitulates skeletal phenotype |