Heterozygous variants in DCC: Beyond congenital mirror movements

OBJECTIVE: To perform a comprehensive characterization of a cohort of patients with congenital mirror movements (CMMs) in Sweden. METHODS: Clinical examination with the Woods and Teuber scale for mirror movements (MMs), neuroimaging, navigated transcranial magnetic stimulation (nTMS), and massive parallel sequencing (MPS) were applied. RESULTS: The cohort is ethnically diverse and includes a total of 7 patients distributed in 2 families and 2 sporadic cases. The degree of MMs was variable in this cohort. MPS revealed 2 novel heterozygous frameshift variants in DCC netrin 1 receptor (DCC). Two siblings harboring the pathogenic variant in c.1466_1476del display a complex syndrome featuring MMs and in 1 case receptive-expressive language disorder, chorea, epilepsy, and agenesis of the corpus callosum. The second DCC variant, c.1729delG, was associated with a typical benign CMM phenotype. No variants in DCC, NTN1, RAD51, or DNAL4 were found for the 2 sporadic CMM cases. However, one of these sporadic cases had concomitant high-risk myelodysplastic syndrome and a homozygous variant in ERCC excision repair like 2 (ERCC6L2). Reorganized corticospinal projection patterns to upper extremities were demonstrated with nTMS. CONCLUSIONS: The presence of chorea expands the clinical spectrum of syndromes associated with variants in DCC. Biallelic pathogenic variants in ERCC6L2 cause bone marrow failure, but a potential association with CMM remains to be studied in larger cohorts.