A de novo frameshift variant in the candidate RBM15 in a proband with congenital mirror movements.

Abstract

Congenital mirror movements (CMM) are involuntary movements of one body side that mirror intentional movements of the opposite side. DCC, NTN1, RAD51, ARHGEF7, and DNAL4 have been associated with CMM. Two thirds of CMM-affected individuals remain without a genetic diagnosis, indicating that variants in additional genes need to be discovered. We report on a 27-year-old female with CMM of the hands. Trio exome sequencing in the proband and healthy parents did not reveal a likely pathogenic variant in one of the CMM-associated genes, but a de novo heterozygous frameshift variant c.523dup; p.(Ser175Lysfs*8) in the candidate RBM15. The variant results in only partial nonsense-mediated mRNA decay of RBM15 transcripts in the proband's lymphoblastoid cells. RBM15 encodes an RNA binding protein involved in alternative splicing besides other processes. Dcc alternative splicing generates Dcc_long and Dcc_short isoforms which are important for commissural axon midline crossing. We tested if Rbm15 regulates Dcc alternative splicing by using an in vitro minigene assay. Ectopic expression of Rbm15, similar to the splicing factors Nova1 and Nova2, promotes the production of Dcc_long transcripts. The possible link between Rbm15 and Dcc supports a role for Rbm15 in CMM.