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Biallelic mutations in B3GALT6 (HGNC:17978) have been robustly associated with spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures (MONDO_0010075). Multiple independent case reports and multi‐patient studies (PMID:25149931, PMID:29230159) document affected probands presenting with skeletal dysplasia, joint laxity, and variable extra‐skeletal features. These studies report compound heterozygous and homozygous mutations—including missense, frameshift, and other loss‑of‑function variants—that segregate in families consistent with an autosomal recessive inheritance pattern. In particular, segregation in families with affected siblings reinforces the causative role of B3GALT6 in driving the complex skeletal phenotype.
Genetically, affected individuals display a spectrum of variant classes. For example, one study reported the variant c.795A>C (p.Glu265Asp) in a newborn with complex skeletal abnormalities, joint contractures, and bilateral corneal clouding (PMID:25149931). Additional case series have delineated phenotypic overlaps with disorders such as Ehlers‑Danlos syndrome, while distinguishing spondyloepimetaphyseal dysplasia with joint laxity through skeletal dysplasia, short stature, and platyspondyly. Moreover, several studies report segregation of the mutations in families with multiple affected siblings (PMID:29230159).
Functional studies provide crucial insights into pathogenicity mechanisms. In vitro assays show that B3GALT6 mutations lead to a reduction in galactosyltransferase II activity, resulting in impaired glycosaminoglycan synthesis, abnormal proteoglycan glycanation, and disrupted collagen fibril organization. These cellular defects mirror the connective tissue abnormalities observed in patients, supporting a model of loss‑of‑function as the primary disease mechanism. Complementary transcriptome‑wide profiling and immunofluorescence analyses have confirmed these disturbances in extracellular matrix organization.
While the majority of the evidence supports an autosomal recessive etiology for spondyloepimetaphyseal dysplasia with joint laxity, isolated reports of dominant‐acting variants exist. However, these dominant cases display a milder phenotype and, in the context of the severe skeletal dysplasia observed here, do not diminish the overall association strength. No conflicting studies have refuted the relationship between biallelic B3GALT6 mutations and the full spectrum of the skeletal and connective tissue features in this condition.
In summary, the convergence of robust genetic evidence and concordant functional data establishes a strong link between B3GALT6 mutations and spondyloepimetaphyseal dysplasia with joint laxity. The extensive, multi‐family segregation data, coupled with mechanistic insights from genetic and functional studies, underscore its clinical utility for diagnosis and risk stratification.
Key Take‑home Sentence: B3GALT6 represents a critical gene in the pathogenesis of spondyloepimetaphyseal dysplasia with joint laxity, with strong genetic and functional support, making it an essential target for diagnostic evaluation.
Gene–Disease AssociationStrongMultiple independent probands (over 15 across several studies, e.g. PMID:25149931, PMID:29230159) exhibit compound heterozygous and homozygous mutations with familial segregation and concordant functional evidence. Genetic EvidenceStrongConsistent findings across case reports and multi‐patient studies reveal biallelic loss‐of‐function mutations, including missense and frameshift variants, that segregate in an autosomal recessive manner. Functional EvidenceModerateIn vitro assays demonstrate significantly decreased galactosyltransferase activity, impaired glycosaminoglycan synthesis, and abnormal collagen organization, matching the patient phenotype. |