DCC loss-of-function variants were first reported in two large pedigrees with congenital mirror movements in 2010 (Srour et al., PMID: 20431009). Mirror movements 1 and/or agenesis of the corpus callosum (MONDO:0100515) is an autosomal dominant condition with incomplete penetrance that may present with isolated congenital mirror movements and/or isolated complete or partial agenesis of the corpus callosum. Intellectual abilities range from normal to borderline impaired; asymptomatic carriers have been reported. Of note, three probands with homozygous DCC loss-of-function variants and autosomal recessive familial horizontal gaze palsy with progressive scoliosis, 2 (OMIM #120470) have also been reported (28250456, 33141514); these individuals have not been included in this curation.
At least 10 DCC loss-of-function (nonsense, frameshift) variants and 8 missense variants have been reported in 19 probands across 5 publications (PMID: 20431009, 21242494, 24808016, 28250454, 31697046). Additional evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function.
This gene-disease relationship is also supported by experimental evidence including a demonstrated physical interaction with NTN1 (Mirror Movements 4, OMIM 618262) (PMID 8861902) and expression studies demonstrating expression in commissural axons in the rat spinal cord and localization of DCC to the developing mouse peripheral nervous system (PMID: 8861902, 11335129). Two mouse models have been reported: a knock-out with abnormal movement and defects in commissural axonal projections (PMID:9126737) and a spontaneous mouse mutant, Dcc Kanga, that displays a distinctive hopping gait resulting from mirror movements of the hind legs (PMID: 12451134).
In summary, there is definitive evidence to support the relationship between DCC and autosomal dominant mirror movements 1 and/or agenesis of the corpus callosum (MONDO:0100515). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations gene curation expert panel on July 26, 2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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