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DCC encodes the transmembrane receptor for the guidance cue netrin-1, playing a critical role in commissural axon targeting during nervous system development. Heterozygous germline variants in DCC cause familial congenital mirror movements (CMM; MONDO:0016558), an autosomal dominant axonal guidance disorder characterized by involuntary contralateral limb movements, typically of the hands (HP:0001335). Affected individuals present in early childhood with variable expressivity and incomplete penetrance, and may demonstrate associated strabismus or other cranial dysinnervation features. Genetic testing of DCC informs diagnostic evaluation, recurrence risk counseling, and exclusion of phenocopies.
In a landmark Neurology study, 6 familial and 20 simplex CMM cases underwent sequencing of DCC and RAD51, revealing DCC variants in 4 unrelated pedigrees, including 3 novel truncating mutations segregating with disease, one intragenic deletion, one frameshift variant, and five missense alleles absent from >4,300 ethnically matched controls (PMID:24808016). The overall burden of rare pathogenic DCC variants was significantly enriched in CMM cases compared with controls (p < 0.001) (PMID:24808016).
Segregation analysis demonstrated co-segregation of heterozygous DCC alleles with mirror movements in multiple affected relatives per pedigree, consistent with autosomal dominant inheritance and reduced penetrance. Conversely, an independent four-generation Italian family with CMM showed no pathogenic variants in DCC or RAD51, indicating genetic heterogeneity (PMID:30713853). These data support dominant transmission with variable expression and highlight the need for comprehensive gene panels when DCC testing is negative.
Reported DCC mutations span predicted loss-of-function alleles (n = 12) and missense variants (n = 14) distributed across extracellular fibronectin type III and intracellular domains. Exemplary alleles include the frameshift variant c.1336_1337insAGCC (p.Arg446fs) disrupting the transmembrane region. All pathogenic DCC variants are absent or extremely rare in population databases, and no recurrent founder change has been observed. An updated review catalogued 26 DCC mutations associated with mirror movements, agenesis of the corpus callosum, or developmental split-brain syndromes (PMID:29068161).
Mechanistic studies confirm a loss-of-function disease mechanism. A CMM-associated variant in the WAVE regulatory complex–interacting motif of DCC (p.Arg1343His) abolishes DCC–WRC binding and impairs netrin-1–mediated axon guidance in rodent neurons and Drosophila models (PMID:39353037). RNA-binding Nova proteins regulate Dcc alternative splicing in the spinal cord, and restoration of correct splicing rescues commissural axon pathfinding defects in Nova knockout mice (PMID:27223328). Cellular assays further demonstrate that pathogenic DCC missense mutations reduce surface expression and filopodial responses to netrin-1.
Integration of robust genetic segregation, case–control enrichment, and mechanistic data supports a Strong gene–disease validity classification under ClinGen criteria. The autosomal dominant inheritance of DCC-related CMM, coupled with functional concordance in in vitro and in vivo models, establishes DCC testing as clinically actionable. Inclusion of DCC in diagnostic gene panels for congenital mirror movements facilitates precise diagnosis, prognostic counseling, and family planning.
Key Take-home: Heterozygous DCC variants are a clinically actionable cause of familial congenital mirror movements, guiding genetic diagnosis and management.
Gene–Disease AssociationStrongSegregating DCC variants in 4 unrelated families and significant case–control enrichment (p < 0.001) Genetic EvidenceStrongIdentification of DCC alleles in 4 familial pedigrees, co-segregation data, and significant burden in 26 cases versus 4300 controls Functional EvidenceModerateCellular and animal models show disrupted netrin-1/DCC signaling and rescue of pathfinding defects in splice and interaction assays |