Diagnostic yield of genome sequencing in children with progressive movement disorders

Abstract Childhood-onset movement disorders are clinically and genetically heterogeneous, with over 500 implicated genes. Standard clinical genetic testing, including exome sequencing, has limited sensitivity for certain variants, including repeat expansions, structural variants, copy number variants and deep intronic changes. We evaluated the diagnostic utility of short-read whole-genome sequencing (srWGS) and, in selected cases, long-read whole-genome sequencing (lrWGS) in a real-world cohort of children and young adults with early-onset progressive movement disorders and prior non-diagnostic genetic testing. One hundred individuals (A molecular diagnosis was achieved in 27% (27/100) of cases, and candidate variants were identified in an additional 33% (33/100). Among solved cases, 81.5% (22/27) were identified from exome-level data, while 18.5% (5/27) required genome-level analysis to detect variants such as repeat expansions in HTT and FXN, an intragenic duplication in MECP2, an Alu insertion in ATM and a deletion in FA2H. Genome-level analysis contributed an additional diagnostic yield of only 5% (5/100). Notably, in 33.3% (9/27) of solved cases, variants had been reported previously but not recognized as diagnostic. LrWGS of 14 unsolved trios did not yield additional diagnoses. SrWGS provided a modest incremental yield over exome sequencing in early-onset movement disorders, with most diagnoses achieved through reanalysis of exome-level data. Findings highlight the importance of iterative variant interpretation and the need for improved analytic pipelines to fully realize the potential of genome sequencing.