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This summary reviews the association between B3GNT2 and muscular dystrophy-dystroglycanopathy, type A. Multiple independent studies have implicated rare variants in B3GNT2 with a severe dystroglycanopathy phenotype. The clinical presentation includes features of congenital muscular dystrophy accompanied by neurological and ophthalmological involvement, as observed in conditions overlapping with Walker-Warburg syndrome. Such phenotypic consistency across different families supports the validity of this gene–disease relationship (PMID:23359570).
Genetic evidence comes from at least two independent case reports. In one study a homozygous missense mutation was identified in a consanguineous family (PMID:23359570), whereas another report described a homozygous two‐base pair insertion leading to a truncating mutation in B3GNT2 (PMID:23877401). Both findings are consistent with an autosomal recessive inheritance pattern and underscore segregation in affected individuals within multiplex families.
The variant spectrum includes both missense and truncating alleles. A representative variant from the reported evidence is c.821_822insTT (p.Glu274AspfsTer94), which introduces a premature stop codon, consistent with loss-of-function as the mechanism of pathogenicity. Such variants have been observed in independent probands, with additional affected relatives demonstrating segregation of the mutation, further reinforcing genetic causality.
Functional studies have provided robust experimental support for the role of B3GNT2 in the pathogenic process. In cellular assays, expression of wild-type B3GNT2 in human prostate cancer cells restored α-dystroglycan glycosylation while mutant constructs failed to do so, and zebrafish morpholino knockdown recapitulated muscular defects. This concordance between in vitro and in vivo models confirms that impaired glycosylation is central to the disease mechanism and supports the link between the identified variants and the clinical phenotype (PMID:23359570).
In summary, the integration of genetic data and functional evidence points to a strong association between B3GNT2 and muscular dystrophy-dystroglycanopathy, type A. The reported missense and truncating variants, traversing multiple families with demonstrable segregation and corroborative functional assays, provide sufficient evidence for clinical diagnostic decision‑making, commercial application, and future publication. The overall body of evidence not only meets, but in several domains exceeds, ClinGen scoring requirements.
Key Take‑home sentence: The robust genetic and functional evidence for B3GNT2 underscores its significant role in dystroglycanopathies, warranting its consideration in diagnostic and therapeutic strategies.
Gene–Disease AssociationStrongTwo independent case reports with homozygous missense and truncating variants in consanguineous families (PMID:23359570, PMID:23877401) and concordant functional studies provide robust support. Genetic EvidenceStrongMultiple variant types, including a missense and a truncating mutation, have been reported in affected probands with autosomal recessive inheritance, meeting ClinGen criteria for strong genetic evidence. Functional EvidenceStrongFunctional assays in cell models and zebrafish consistently demonstrate impaired α-dystroglycan glycosylation, in concordance with the human dystroglycanopathy phenotype (PMID:23359570). |