Family-Based Genome Analysis Identifies Clinically Relevant de novo Variants in Pediatric Dystonia (4446)

Objective: Application of advanced genomic technologies capturing a greater variety of genetic variants identifies known and novel inherited/de novo variants contributing to dystonia etiology in parent-child trios with no genetic diagnosis using routine clinical genetic tests.

Background: Dystonia is a movement disorder characterized by sustained/intermittent muscle contractions. It can be genetically inherited, acquired from brain injury, or arise spontaneously in individuals with no family history of the disorder. To date, variants in ~15 genes are implicated in different forms of dystonia, designated as DYT loci, the majority of which follow autosomal dominant inheritance. Clinical and genetic heterogeneity of dystonia challenges the identification of its underlying genetic risk, and hence genetic diagnosis.

Design/Methods: We performed whole genome sequencing (WGS) on nine families with dystonia (8 families) and dyskinesia (one family) with no genetic causes found from prior genetic tests. We sequenced the affected individuals, their parents, and siblings (n=30). We assessed rare genetic variants, including single nucleotide variants, small insertions and deletions, copy number and structural variants for potential clinical relevance based on their predicted damage to genes implicated in dystonia/related disorders.

Results: A de novo pathogenic loss-of-function (LoF) frameshift insertion in PRRT2 was identified in an affected individual with paroxysmal kinesigenic dyskinesia and epilepsy. LoF variants in PRRT2 are reported in individuals with dystonia/paroxysmal kinesigenic dyskinesia. We also identified a de novo frameshift deletion in TCEAL5 on the X chromosome of a male individual with generalized dystonia, choreoathetosis and global developmental delay. TCEAL5 is highly expressed in brain with no known function. Four other de novo missense variants of uncertain significance from 3 families were present in SEC16A, BUD23, LAMA5 and STAB2, awaiting further research determining their relevance.

Conclusions: We demonstrate the power of family-based WGS to uncover the contributions of genetic variants to dystonia/dyskinesia liability that were undetected using routine clinical gene panel testing.

Disclosure: Dr. Adhamimojarad has nothing to disclose. Dr. Yin has nothing to disclose. Dr. Backstrom has nothing to disclose. Dr. Yuen has nothing to disclose. Dr. Soman has nothing to disclose.