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Brachydactyly type C (BDC) is an autosomal dominant disorder characterized by shortening of the middle phalanges of the second, third, and fifth fingers, hyperphalangy, a short first metacarpal, and ulnar deviation of the index finger. Growth Differentiation Factor 5 (GDF5; [HGNC:4220]) encodes a BMP-family ligand essential for chondrogenesis and joint morphogenesis. Heterozygous pathogenic variants in GDF5 underlie BDC by reducing ligand activity, leading to functional haploinsufficiency. Clinical features overlap with Angel-shaped phalango-epiphyseal dysplasia but genetic and radiographic evidence support a unified GDF5-dependent spectrum ([PMID:22828468]).
Isolated case reports have identified several novel GDF5 variants in diverse populations. A Mexican patient presenting with BDC and ASPED features harbored a unique proregion mutation, confirming spectrum overlap ([PMID:22828468]). A Korean girl with classic BDC but no foot involvement carried c.1312C>T (p.Arg438Cys) ([PMID:23483675]). An 11-year-old Chinese patient exhibited a heterozygous frameshift, c.349del (p.Ala117fs), resulting in premature termination and haploinsufficiency ([PMID:35819086]). Compound heterozygosity for c.956G>T (p.Gly319Val) and c.1073T>C (p.Ile358Thr) revealed that p.Gly319Val has pronounced loss-of-function in luciferase and chondrogenesis assays, whereas p.Ile358Thr behaves near‐wild-type, indicating variable penetrance ([PMID:25994865]).
A foundational multi-family study of BDC in 10 unrelated pedigrees described heterozygous frameshift and missense mutations in GDF5, with co-segregation in a four-generation family and nonpenetrance in one carrier ([PMID:12357473]). Nine additional probands/families carried diverse variants, including missense substitutions within the active domain and multiple frameshifts across the propeptide, confirming locus homogeneity. Overall, at least 12 probands from 10 families demonstrate a consistent autosomal dominant inheritance pattern with variable expressivity and one instance of nonpenetrance.
The variant spectrum comprises nine missense changes (e.g., p.Arg438Cys, p.Cys498Arg) and three frameshift/nonsense alleles (e.g., p.Ala117fs) affecting both propeptide and mature domains. No recurrent or founder alleles have been established, and population frequencies are negligible, consistent with rare, private pathogenic variants. Phenotypic spectrum includes short first metacarpal (HP:0010034), ulnar deviation of the second finger (HP:0009464), and delayed skeletal maturation (HP:0002750).
Functional assays support a haploinsufficiency mechanism. Mutant GDF5 polypeptides with missense changes in the active domain show impaired disulfide-linked dimer formation in vitro, and frameshift alleles abolish mature ligand secretion. Luciferase reporter and chondrogenesis assays reveal significantly reduced signaling for p.Gly319Val, and western blot shows decreased protein levels, concordant with human phenotype ([PMID:12357473], [PMID:25994865]).
Integration of genetic and experimental data yields a Strong gene–disease association: heterozygous GDF5 variants cause autosomal dominant BDC via haploinsufficiency. Additional evidence from larger cohorts and in vivo models may further elucidate penetrance and modifier effects. Key take-home: GDF5 sequencing is critical for molecular diagnosis of BDC and informs genetic counseling for affected families.
Gene–Disease AssociationStrong12 probands across 10 families with segregation and functional concordance Genetic EvidenceStrong12 probands with heterozygous GDF5 variants (including 9 missense and 3 frameshift variants) and segregation in a multi-generation family Functional EvidenceModerateIn vitro assays demonstrate loss-of-function via impaired dimerization and signaling consistent with haploinsufficiency |