B4GALT7 – Spondylodysplastic Ehlers-Danlos Syndrome

Biallelic pathogenic variants in B4GALT7 cause the autosomal recessive spondylodysplastic Ehlers-Danlos syndrome (spEDS-B4GALT7; MONDO:0020682), characterized by short stature, radioulnar synostosis, bowing of long bones, skin hyperextensibility and joint laxity. The inheritance is autosomal recessive with compound heterozygous or homozygous variants disrupting proteoglycan biosynthesis in the Golgi apparatus. Functional studies confirm that loss or hypomorphic changes in β1,4-galactosyltransferase 7 impair glycosaminoglycan chain initiation, leading to the connective tissue and skeletal phenotype.

Genetic Evidence: To date, eight unrelated probands with spEDS-B4GALT7 have been reported, including one compound heterozygote carrying c.122T>C (p.Leu41Pro) and c.808C>T (p.Arg270Cys) and a Moroccan patient with homozygous c.829G>T (p.Glu277Ter) (PMID:23956117, PMID:28882145). Additional missense mutations c.557C>A (p.Ala186Asp) and c.617T>C (p.Leu206Pro) segregate in an affected sib-pair with unaffected heterozygous parents (PMID:10506123). There are no reported affected relatives beyond these sibships.

Variant Spectrum: Five pathogenic variants have been described in spEDS-B4GALT7: two recurrent missense substitutions (p.Ala186Asp, p.Leu206Pro), a hypomorphic p.Arg270Cys, a novel p.Leu41Pro, and a truncating p.Glu277Ter. All meet criteria for damaging or null alleles disrupting enzyme function.

Segregation and Case Series: The biallelic inheritance pattern is confirmed in multiple families; unaffected parents and siblings are heterozygous carriers. A total of 8 probands across 6 families fulfill diagnostic criteria for spEDS-B4GALT7 with molecular confirmation.

Functional & Experimental Evidence: Enzymatic assays demonstrate that p.Leu206Pro abolishes enzyme activity, p.Ala186Asp impairs donor substrate binding, and p.Arg270Cys severely compromises acceptor binding and glycosaminoglycan chain initiation (PMID:20809901). Hypomorphic zebrafish b4galt7 models recapitulate short stature, craniofacial defects and reduced sulfated glycosaminoglycans, confirming pathomechanism in vivo (PMID:31862401).

Integration & Clinical Utility: The concordance of biallelic deleterious B4GALT7 variants in eight unrelated individuals, robust functional assays, and an animal model provide strong evidence for a definitive gene-disease relationship. Molecular testing of B4GALT7 should be pursued in individuals with short stature, skeletal dysplasia, and connective tissue laxity. This association supports diagnostic decision-making, genetic counseling, and future therapeutic research.

References

• American journal of medical genetics. Part A • 2013 • Redefining the progeroid form of Ehlers-Danlos syndrome: report of the fourth patient with B4GALT7 deficiency and review of the literature PMID:23956117
• The Journal of biological chemistry • 1999 • Molecular basis for the progeroid variant of Ehlers-Danlos syndrome. Identification and characterization of two mutations in galactosyltransferase I gene PMID:10506123
• The Biochemical journal • 2010 • Biochemical and thermodynamic characterization of mutated β1,4-galactosyltransferase 7 involved in the progeroid form of the Ehlers-Danlos syndrome PMID:20809901
• Matrix biology : journal of the International Society for Matrix Biology • 2020 • Hypomorphic zebrafish models mimic the musculoskeletal phenotype of β4GalT7-deficient Ehlers-Danlos syndrome PMID:31862401
• Orphanet journal of rare diseases • 2017 • Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome PMID:28882145

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