Molecular Characteristics

DCC is composed of four structurally distinct, evolutionarily conserved regions: four extracellular Ig-like domains, six extracellular fibronectin type III-like (FN3) domains, a transmembrane domain, and an intracellular domain with three conserved P motifs. Each region of DCC appears to have a unique functional role required for the transduction of NTN1 signaling.

Monoallelic and biallelic, germline DCC pathogenic variants disrupt commissural axon guidance. These disruptions impair the normal development and function of tracts such as the corticospinal tract and corpus callosum. Monoallelic DCC mutations cause congenital mirror movements (MMs; MIM# 157600) in association with abnormal midline crossing of the corticospinal tract, isolated agenesis of the corpus callosum (iACC; MIM# 217990), or both. Alternatively, biallelic DCC mutations leading to predicted loss-of-function cause developmental split-brain syndrome (DSBS; MIM# 617542), a more complex syndrome associated with ACC as well as widespread failure of commissural tracts throughout the rest of the central nervous system, with or without MMs.

Monoallelic or biallelic missense and monoallelic, predicted loss-of-function (LoF) DCC mutations may cause MMs, iACC, or both. Alternatively, biallelic, predicted LoF DCC mutations cause DSBS. Monoallelic DCC variants associated with MMs and iACC are associated with incomplete penetrance. In contrast, biallelic DCC variants associated with DSBS appear to be fully penetrant. Monoallelic DCC mutations are also associated with variable expressivity and affected individuals within one family may present with MMs, iACC, or both. DCC residues altered by a missense mutation are usually conserved throughout vertebrate evolution and are either private or found at a minor allele frequency of less than 0.5% in population genetic databases.

The observed structure of pedigrees with monoallelic, predicted LoF DCC mutations has suggested a sex-bias in MMs and iACC phenotype expression. Indeed, within these pedigrees a significant proportion of males displayed MMs, while iACC was almost exclusively detected in females. 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 population genetic databases.

More recently, monoallelic, germline DCC missense variants were reported in the pathophysiology of congenital hypogonadotropic hypogonadism (CHH; MIM# 147950), although this association is pending confirmation.

At the time of writing, approximately 40 families with MMs, iACC, DSBS and/or CHH have been described. Of these, half have missense (20/40, 50%) and half have predicted LoF (20/40, 50%) variants. Most affected individuals presented with monoallelic DCC variants (35/40, 87.5%), while the remainder presented with biallelic DCC variants (5/40, 12.5%). Incomplete penetrance was observed in approximately half the families (21/40, 52.5%).    

Suspected pathophysiologic mechanisms:
Commissural axons form connections between the left and right sides of the brain that are required for the transfer and integration of information generated by sensory, motor, and associative neurons. These connections are defined anatomically as either commissures or decussations. While commissures cross the midline to form predominantly homotopic connections, decussations descend or ascend along the neuroaxis before crossing the midline to form connections with different neuronal populations.

•    Mirror movements
DCC-mirror movements (MMs) are observed in association with midline axon guidance defects, evidenced by decreased crossing of descending corticospinal motor projections at the pyramidal decussation. This reduction of crossed projections occurs in conjunction with a relative, reciprocal increase of uncrossed projections. Concordantly, unilateral transcortical stimulation of the primary hand motor area elicits both normal, contralateral, and abnormal, ipsilateral motor evoked potentials in individuals with DCC-MMs. As a result, DCC-MMs are thought to originate from the bilateral transmission of motor commands through normally crossed and abnormally uncrossed, fast-conducting corticospinal tract projections in the spinal cord.

•    Agenesis of the corpus callosum
DCC-agenesis of the corpus callosum (ACC) describes the partial or complete absence of the corpus callosum and is characterized by the failure of callosal axons to cross the midline. Individuals may present with complete or partial ACC. A subset of these individuals may also present with mirror movements, which suggests that DCC-ACC may frequently present as part of a global disorder of midline crossing. Recent evidence posits a critical role for DCC and NTN1 during interhemispheric fissure remodeling, a process required for normal corpus callosum development. It is hypothed that loss of DCC or NTN1 function during early brain developmental perturbs interhemispheric fissure remodeling, preventing the formation of a permissible interhemispheric substrate for callosal axons to cross the midline.

•    Developmental split-brain syndrome
Biallelic, DCC mutations leading to predicted loss of function are associated with developmental split-brain syndrome (DSBS), a complex syndrome associated with a broad disorganization of white-matter tracts throughout the central nervous system. The features of DSBS include absence of all commissures (including the corpus callosum, anterior and posterior commissures), brainstem defects (including hypoplasia of the pons and midbrain), horizontal gaze palsy and progressive scoliosis with a variable age of onset. The pathogenesis of progressive scoliosis is unknown but may stem from defective spinal commissural interneurons or abnormal development of extrapyramidal projections. The horizontal gaze palsy observed in DSBS affected individuals appears to originate from hindbrain midline axon guidance defects in tracts that control conjugate horizontal eye movement. Individuals with DSBS have a poor developmental outcome compared to individuals with DCC-MMs and DCC-iACC, likely attributed to additional brain abnormalities affecting the formation of other commissural tracts.

Diagnostic testing:
Testing requires sequencing of the coding exons and flanking intronic regions of the DCC gene (LRG_1107), either by traditional Sanger sequencing or massively parallel sequencing methodology (panel testing, exome, or genome). Determining the pathogenicity of novel variants requires the use of population genetic data, computational and predictive tools, segregation in additional family members and molecular/functional studies to generate sufficient evidence that a detected variant is causal of the individual’s condition. Whether the phenotype is consistent with the disease should also be considered.

If a pathogenic variant is identified in the index patient, genetic testing of the parents, unaffected offspring and extended family can be offered for genetic counselling, while options such as prenatal diagnosis and pre-implantation genetic diagnosis can be explored.