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Autosomal recessive omodysplasia is a rare short-limb skeletal dysplasia caused by biallelic variants in the GPC6 gene and follows an autosomal recessive inheritance pattern. Affected individuals exhibit rhizomelic short stature (HP:0008905), severe proximal limb shortening, limited elbow and knee mobility, and distinctive craniofacial anomalies, differentiating it from the dominant FZD2-related form.
Genetic evidence includes two affected brothers from a consanguineous Pakistani family harboring a homozygous deletion of exon 6 and a nonsense variant c.700C>T (p.Arg234Ter) in GPC6 (2 probands) (PMID:32655339). In a separate pedigree, five siblings presented with a homozygous missense variant c.511C>T (p.Arg171Trp) (5 probands) (PMID:37353964).
Segregation analysis in both families demonstrated co-segregation of each variant with disease status: one additional affected sibling in the first family and four in the second, totaling five additional affected relatives.
The variant spectrum comprises a complete exon deletion and a premature termination codon (LoF), alongside a recurrent hypomorphic missense allele. The p.Arg171Trp variant results in partial GPC6 function, correlating with a milder skeletal phenotype compared to complete loss of function.
Functional assessment using a Hedgehog reporter assay revealed that p.Arg171Trp significantly reduces Hedgehog pathway stimulation relative to wild-type GPC6, confirming a loss-of-function mechanism with residual activity and supporting genotype–phenotype correlations.
Overall, seven probands across two unrelated families with concordant clinical features and robust functional data yield a Strong gene–disease association. GPC6 mutation analysis is critical for definitive diagnosis, genetic counseling, and tailoring management of autosomal recessive omodysplasia.
Key Take-home: Biallelic loss-of-function and hypomorphic GPC6 variants underlie autosomal recessive omodysplasia and should be included in skeletal dysplasia genetic panels.
Gene–Disease AssociationStrongSeven probands across two unrelated families with biallelic GPC6 variants and concordant functional data Genetic EvidenceStrong7 probands in 2 families with confirmed biallelic loss-of-function and missense variants Functional EvidenceModerateHedgehog reporter assays show significant reduction in GPC6-mediated signaling for p.Arg171Trp hypomorphic variant |