Objective: To identify genetic causes of paediatric movement disorders in a large multi-ethnic cohort of patients by genetic investigations.

Background: Pediatric movement disorders which are usually part of complex neurodevelopmental disorders comprise a wide group of neurological diseases with highly variable, heterogeneous and often complex clinical presentation. Although causative mutations in more than a few hundred genes have been associated with various movement disorders, many patients remain without a defined genetic diagnosis [1]. The SYNaPS Study, which is IRB/ethics approved and aimed at analysing unexplained ultra-rare neurological conditions, aim to identify underlying genetic causes in patients with pediatric movement disorders by high-throughput genetic investigations.

Method: As part of SYNaPS study a large cohort of well-phenotyped families affected by childhood and early-onset movement disorders were recruited from multiple paediatric neurology clinicns around the world with a diverse ethnic background. The patients were genetically and clinically investigated through the program. Exome sequencing was performed for probands of around 500 families with any forms of movement disorders. Some of the unsolved individuals were subjected to a combination of SNP-Array genotyping/homozygosity mapping, whole genome sequencing, long-read sequencing and coupled with deep-phenotyping.

Results: Overall, in this study we manage to resolve around 50% of the patients with movement disorders. We also uncovered novel disease-causing genes in various families. Re-annotating/re-analysing the exome data along with more extensive data sharing and also employing homozygosity mapping in some of the families increased the rate of diagnosis.

Conclusion: We made a molecular diagnosis for around half of the families and characterised multiple new genes and defined new ultra-rare movement disorders. Additionally, an accurate genetic diagnosis provided either disease-specific therapy or improved the management for some affected individuals with a genetic diagnosis, underlining the significance of early and specific diagnosis.

References: 1) Cordeiro D, Bullivant G, Siriwardena K, Evans A, Kobayashi J, Cohn RD, Mercimek-Andrews S. Genetic landscape of pediatric movement disorders and management implications. Neurology Genetics. 2018 Oct 1;4(5):e265.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-genetic-basis-of-paediatric-movement-disorders-experience-from-the-synaps-study/