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Brachydactyly type E (BDE) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, predominantly affecting postaxial rays. Isolated BDE is rare, with most cases lacking a molecular diagnosis until HOXD13 heterozygous missense variants were identified (PMID:12649808).
Initial studies described two unrelated families harboring heterozygous missense mutations in the HOXD13 homeodomain (p.Ser316Cys) that co-segregate with brachydactyly of metacarpals and phalanges (PMID:12649808). These variants were proposed to alter DNA-binding affinity without grossly affecting transcript levels.
A recent case report of a Polish family revealed a novel nonsense variant c.820C>T (p.Arg274Ter) segregating in a female proband and her affected father with isolated BDE, expanding the allelic spectrum to truncating mutations (PMID:22233338).
Overall, three unrelated families (two with monoallelic missense, one with nonsense) and a total of three probands support an autosomal dominant inheritance of HOXD13-related BDE, with at least one additional affected relative confirmed.
Functional in vitro assays for homeodomain missense variants demonstrate mixed gain- and loss-of-function in DNA-binding, consistent with a dominant effect on transcriptional regulation of limb patterning genes (PMID:12649808). No studies have conclusively disputed the HOXD13–BDE link.
Integration of genetic and experimental data establishes a moderate clinical validity for HOXD13 in isolated BDE. HOXD13 sequencing should be considered in patients with metacarpal and metatarsal shortening. Key take-home: heterozygous HOXD13 mutations reliably underlie isolated BDE, informing diagnostic genetic testing.
Gene–Disease AssociationModerateThree unrelated families (two with monoallelic missense, one with nonsense) total three probands with segregation evidence Genetic EvidenceModerateThree families with cosegregating heterozygous HOXD13 variants (two missense, one nonsense) Functional EvidenceLimitedIn vitro homeodomain assays show altered DNA-binding for missense variants ([PMID:12649808]) |