FV 1031. Whole Exome Sequencing for Children with Dyskinetic Movement Disorder

Background: Dyskinetic movement disorders are a group of disorders with similar clinical manifestation consisting of neurodegenerative and neurometabolic disorders as well as cerebral palsy (CP). Dyskinetic movement disorders are rare conditions and diagnostically hard to detect. In contrast to CP, which is a nonprogressive condition and mainly caused by hypoxia-ischemia during birth, the subgroup of neurodegenerative and neurometabolic movement disorders are progressive conditions and a genetic contribution to the pathogenesis of these conditions has to be taken into account.

Aims: We aim to investigate the genetics of dyskinetic movement disorders and to gain insights by the identification of causative genetic variants in known and novel candidate genes using whole exome sequencing (WES) in patient parent trios.

Question: Is there a genetic contribution to dyskinetic movement disorders and, if any, how are the genetic causes characterized? What proportion of cases with dyskinetic movement disorder can be explained by a genetic cause and is trio-based WES a suitable method for the detection of causative variants in these patients?

Methods: We performed WES of dyskinetic movement disorder patients and their parents (trios). To date, our cohort consists of five patients with a clear diagnosis of CP, eight patients in whom CP could be excluded clinically and by medical imaging, and three patients with a dyskinetic movement disorder of unclear etiology. We sequenced the trios as 100-bp paired-end runs on a HiSeq4000 platform (Illumina, San Diego, California, United States). Exome capture was performed using the SureSelect Human All Exon V6 kit (Agilent, Santa Clara, California, United States). Data analysis and variant prioritization were performed using a pipeline developed in-house (Helmholtz Center Munich).

Results: Up to now, we analyzed 16 dyskinetic movement disorder trios and identified a pathogenic or likely pathogenic variant in five of the patients in the genes SLC9A6, SPAST, and AUTS2 (de novo variants, dominant diseases) as well as in the genes MECR and TECPR2 (compound heterozygous variants, recessive diseases). Moreover, we found a compound heterozygote variant of uncertain significance (VUS) in the gene WWOX in one patient. All six patients with monogenetic cause (positive WES incl. VUS) showed progressive presentation and the diagnosis of CP could be excluded clinically and by medical imaging, whereas the five patients with clear diagnosis of CP as well as the three patients with an unclear etiology of the dyskinetic movement disorder all had a negative WES. For the remaining two non-CP cases, where WES did not reveal a causative variant in genes with known disease associations, further investigation is required.

Conclusion: Our results indicate that a substantial proportion of dyskinetic movement disorder cases are due to a monogenic cause. This subgroup consists of unclear cases where CP can be excluded clinically and by MRI. We conclude that trio-based WES seems to be a suitable method for the investigation of causative variants in unclear cases of dyskinetic movement disorder and should be considered in clinical practice.