Diagnostic yield of genome sequencing in children with progressive movement disorders

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 (SVs), copy number variants (CNVs), and deep intronic changes. We evaluated the diagnostic utility of short-read whole genome sequencing (srWGS) and, in selected cases, long-read genome sequencing (lrWGS) in a real-world cohort of children and young adults with early-onset progressive movement disorders and prior nondiagnostic genetic testing. One hundred individuals (<30 years) with progressive movement disorders with a suspected genetic etiology were recruited from a tertiary pediatric movement disorders program. All had prior nondiagnostic testing. SrWGS (Illumina NovaSeq 6000) assessed single nucleotide variants (SNVs), CNVs, SVs, and repeat expansions; lrWGS (Pacific Biosciences) was applied to select unsolved trios. Variants were reviewed by a multidisciplinary team using standard variant interpretation guidelines and phenotype correlation. 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 5% (5/100) only. Notably, in 33.3% (9/27) of solved cases, variants had been previously reported 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.