Heterozygous variants in DCC: Beyond congenital mirror movements

Sebastian Thams; Mominul Islam; Marie Lindefeldt; Ann Nordgren; Tobias Granberg; Bianca Tesi; Gisela Barbany; Daniel Nilsson; Martin Paucar

doi:10.1212/NXG.0000000000000526

Heterozygous variants in DCC: Beyond congenital mirror movements

Neurol Genet. 2020 Oct 20;6(6):e526. doi: 10.1212/NXG.0000000000000526. eCollection 2020 Dec.

Authors

Sebastian Thams¹, Mominul Islam¹, Marie Lindefeldt¹, Ann Nordgren¹, Tobias Granberg¹, Bianca Tesi¹, Gisela Barbany¹, Daniel Nilsson¹, Martin Paucar¹

Affiliation

¹ Department of Clinical Neuroscience (S.T., T.G., M.P.), Karolinska Institutet; Department of Neurology (S.T., M.P.), Karolinska University Hospital; Department of Neurophysiology (M.I.), Karolinska University Hospital; Department of Pediatric Neurology (M.L.), Astrid Lindgren's Hospital; Department of Clinical Genetics (A.N., B.T., G.B.), Karolinska University Hospital; Department of Molecular Medicine and Surgery (A.N., B.T., G.B., D.N.), Karolinska Institutet; and Department of Neuroradiology (T.G.), Karolinska University Hospital, Stockholm, Sweden.

Abstract

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.