Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Abstract

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

DCCmutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome

“…Germline transmission of the mutant allele, except for a p.(Gly803Arg) mutation that arose de novo, was confirmed in all pedigrees where parental genotypes were available (Méneret et al., ). DCC ‐MMs and DCC ‐iACC are both associated with reduced penetrance: MMs ≈42% penetrance and iACC ≈26% penetrance (Marsh et al., ). In contrast, DSBS appears to be fully penetrant.…”

“…The importance of the 4th, 5th, and 6th FN3 domains are highlighted by the significant enrichment of DCC missense mutations linked to MMs and/or iACC within these NTN1 binding regions compared with missense variants located in these domains in the ExAC (Figure A and B) (Marsh et al., ). This enrichment is most significant for monoallelic, missense mutations linked to iACC (five out of nine; 56%) and suggests that missense mutations may cause disease through different, perhaps more complex mechanisms compared with those mutations leading to predicted LoF and haploinsufficiency.…”

“…The neuronal populations that comprise each of these tracts are molecularly distinct and uniquely employ DCC and NTN1 signaling to reach their contralateral targets (Fothergill et al., ; Molyneaux, Arlotta, Menezes, & Macklis, ). Therefore, a missense or predicated LoF DCC mutation may differentially affect commissural versus subcerebral axon trajectories, thus leading to iACC, MMs or both (Marsh et al., ). Although these observations do support the hypothesis that distinct disease mechanisms contribute to DCC ‐MMs or DCC ‐iACC, additional functional investigations are required to confirm this correlation.…”

Loss of Dcc in the spinal cord is sufficient to cause a deficit in lateralized motor control and the switch to a hopping gait

“…However, viable adult mice homozygous for a truncated, likely hypomorphic, allele of Dcc named Dcc kanga were later discovered. For example, Dcc kanga mice are missing the corpus callosum, which is normally responsible for interhemispheric inhibition between motor cortices (Meyer et al, 1995), and whose disruption has been linked to congenital MM in humans (Lepage et al, 2012;Marsh et al, 2017). Despite a clear problem with lateralized motor control, the disrupted neuronal structure responsible for the hopping phenotype in Dcc kanga mice remains unclear.…”

“…Recently, one study performed a targeted deletion of Dcc in the brain and CST (using Emx1-Cre) but did not report a hopping phenotype in these mice (Welniarz et al, 2017). Recently, one study performed a targeted deletion of Dcc in the brain and CST (using Emx1-Cre) but did not report a hopping phenotype in these mice (Welniarz et al, 2017).…”