Exome sequencing in adult neurology practice: Challenges and rewards in a mixed resource setting

• Published in: Clinical neurology and neurosurgery 2018-11, Vol.174, p.48-56
• Main Authors: Nagappa, Madhu, Bindu, Parayil Sankaran, Sinha, Sanjib, Mathuranath, Pavagada S., Taly, Arun B.
• Format: Article
• Language: English
• Subjects: Adults; Ataxia; Deoxyribonucleic acid; Diagnosis; DNA; Epilepsy; Exome; Families & family life; Genes; Genetic disorders; Genetic diversity; Genetic screening; Genetic variance; Genomes; Hereditary spastic paraplegia; Laboratories; Leukoencephalopathy; Metabolism; Minority & ethnic groups; Mitochondrial DNA; Mutation; Neuro-genetic; Neurological disorders; Neurology; Next generation sequencing; Paralysis; Patients; Phenotype; Phenotypes; Phenotypic variations; Variants
• ISSN: 0303-8467; 1872-6968
• DOI: 10.1016/j.clineuro.2018.09.012

•NGS delineates molecular basis of disorders with genetic heterogeneity.•It expands the phenotypic spectrum of known genetic disorders.•It reveals novel genetic variants as well as new phenotypic associations.•It sets platform for research to validate significance of novel genetic variants.•It guides therapy and prognosis in genetic disorders that mimic acquired etiologies. To share the experience of next-generation sequencing (NGS) in delineating molecular basis of neuro-genetic disorders in adults of Indian origin. Adults (aged ≥18 years) evaluated in a single neurology unit at a tertiary-care teaching hospital between August 2014 and September 2016, underwent NGS for (i) sporadic occurrence of neurological disorder where an extensive search did not reveal an acquired cause or (ii) familial or sporadic, uncommon, seemingly genetic disorder where single monogenic cause could not be ascertained based on phenotype. Presence of pathogenic/ likely-pathogenic variants, novel genetic variants, and novel phenotype associations were noted. Clinical phenotypes included: neuromuscular (n = 14), extrapyramidal (n = 8), ataxia (n = 7), leukoencephalopathy (n = 6), spastic paraplegia (n = 5), stroke (n = 4), progressive myoclonic epilepsy (n = 1) and epilepsy with developmental delay (n = 1). Fifty-eight variants were identified in 43 genes in 34 patients, that included 15 (25.9%) reported variants. Genetic diagnosis could be established in 14 (30.43%) subjects. Six probands (13%) harboured previously unreported variants in a clinically relevant gene. Nine probands harboured unreported variants in two or more different genes associated with the clinical phenotype. In three probands we noted novel associations between the phenotype and genetic variation. In all patients, genetic diagnosis impacted treatment and prognostication. We present data of NGS in adults with suspected neuro-genetic disorders from India and this is the first report of its kind. It sets a platform for further basic science research to validate ‘novel’ variants and those of ‘uncertain significance’ as pathogenic or otherwise with specific reference to Indian ethnicity.