Assessment of a Targeted Gene Panel for Identification of Genes Associated With Movement Disorders

Abstract

; for the French Parkinson's and Movement Disorders Consortium IMPORTANCE Movement disorders are characterized by a marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. OBJECTIVE To develop and evaluate a targeted sequencing approach using a customized panel of genes involved in movement disorders. DESIGN, SETTING AND PARTICIPANTS We selected 127 genes associated with movement disorders to create a customized enrichment in solution capture array. Targeted high-coverage sequencing was applied to DNA samples taken from 378 eligible patients at 1 Luxembourgian, 1 Algerian, and 25 French tertiary movement disorder centers between September 2014 and July 2016. Patients were suspected of having inherited movement disorders because of early onset, family history, and/or complex phenotypes. They were divided in 5 main movement disorder groups: parkinsonism, dystonia, chorea, paroxysmal movement disorder, and myoclonus. To compare approaches, 23 additional patients suspected of having inherited cerebellar ataxia were included, on whom whole-exome sequencing (WES) was done. Data analysis occurred from November 2015 to October 2016. MAIN OUTCOMES AND MEASURES Percentages of individuals with positive diagnosis, variants of unknown significance, and negative cases; mutational frequencies and clinical phenotyping of genes associated with movement disorders. RESULTS Of the 378 patients (of whom 208 were male [55.0%]), and with a median (range) age at disease onset of 31 (0-84) years, probable pathogenic variants were identified in 83 cases (22.0%): 46 patients with parkinsonism (55% of 83 patients), 21 patients (25.3%) with dystonia, 7 patients (8.4%) with chorea, 7 patients (8.4%) with paroxysmal movement disorders, and 2 patients (2.4%) with myoclonus as the predominant phenotype. Some genes were mutated in several cases in the cohort. Patients with pathogenic variants were significantly younger (median age, 27 years; interquartile range [IQR], 5-36 years]) than the patients without diagnosis (median age, 35 years; IQR, 15-46 years; P = .04). Diagnostic yield was significantly lower in patients with dystonia (21 of 135; 15.6%; P = .03) than in the overall cohort. Unexpected genotype-phenotype correlations in patients with pathogenic variants deviating from the classic phenotype were highlighted, and 49 novel probable pathogenic variants were identified. The WES analysis of the cohort of 23 patients with cerebellar ataxia led to an overall diagnostic yield of 26%, similar to panel analysis but at a cost 6 to 7 times greater. CONCLUSIONS AND RELEVANCE High-coverage sequencing panel for the delineation of genes associated with movement disorders was efficient and provided a cost-effective diagnostic alternative to whole-exome and whole-genome sequencing.

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

“…To estimate this, we examined the diagnostic rates for families with multiple affected members (either parents or siblings) where a Mendelian genetic etiology can most strongly be presumed. Next we combined our data with the clinically relevant exome diagnostic rates from five recent independent WES studies (Montaut et al, ; Nibbeling et al, ; Ohba et al, ; Pyle et al, ; Sawyer et al, ) of similar undiagnosed families with ataxia obtaining a mean diagnostic rate of 42% from 139 total families (58/139, Table and Table S3). To assess the efficiency of exome sequencing as a diagnostic test we assumed all these families had a Mendelian genetic cause detectable by exome sequencing, thus setting the maximum diagnostic rate at 100% (adjusted to 96% for average exome coverage).…”

“…Collectively, numerous studies evaluating WES and NGS‐based ataxia gene panels have achieved diagnostic rates of 32% across all patients (278/873) and 47% for familial cases (43/92), which improves slightly if focused on WES in familial cases (53%, 30/57, Table S3; Coutelier et al, ; Farwell et al, ; Keogh et al, ; Lee et al, ; Marelli et al, ; Montaut et al, ; Nemeth et al, ; Nibbeling et al, ; Ohba et al, ; Pyle et al, ; Sawyer et al, ; Sun et al, ; van de Warrenburg et al, ). By combining our current data with these studies we evaluated the capability of current exome sequencing and analysis pipelines to achieve a diagnosis of the remaining unsolved ataxia and spasticity cases.…”

Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience

“…Disease features and laboratory findings are often nonspecific in neuromuscular diseases, particularly early or late in disease progression . A comprehensive gene panel is especially useful for heterogeneous diseases as it facilitates diagnosis despite uncertain disease etiology or atypical presentation, and can partly compensate for variable levels of clinical acumen/assessment and/or limited clinical information . However, detailed clinical information should guide genetic diagnosis and reduce turnaround time.…”

“…The diagnostic success of NGS is linked to the cohort inclusion criteria stringency; lower stringency leads to lower diagnostic success . We did not implement strict inclusion criteria.…”

“…15,16 A comprehensive gene panel is especially useful for heterogeneous diseases as it facilitates diagnosis despite uncertain disease etiology or atypical presentation, and can partly compensate for variable levels of clinical acumen/assessment and/or limited clinical information. 10,[17][18][19] However, detailed clinical information should guide genetic diagnosis and reduce turnaround time. Genetic testing does not replace clinical workup.…”