• Christopher Grunseich, Nathan Sarkar, Joyce Lu, Mallory Owen, Alice Schindler, Peter A Calabresi, Charlotte J Sumner, Ricardo H Roda, Vinay Chaudhry, Thomas E Lloyd, Thomas O Crawford, S H Subramony, Shin J Oh, Perry Richardson, Kurenai Tanji, Justin Y Kwan, Kenneth H Fischbeck, and Ami Mankodi.
• Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA christopher.grunseich@nih.gov ami.mankodi@nih.gov.
• J. Neurol. Neurosurg. Psychiatr. 2021 Nov 1; 92 (11): 1186-1196.

BackgroundWe used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres.MethodsWES was performed on 66 individuals with neurogenetic diseases using candidate gene filters and stringent algorithms for assessing sequence variants. Pathogenic or likely pathogenic missense variants were interpreted using in silico prediction tools, family segregation analysis, previous publications of disease association and relevant biological assays.ResultsMolecular diagnosis was achieved in 39% (n=26) including 59% of childhood-onset cases and 27% of late-onset cases. Overall, 37% (10/27) of myopathy, 41% (9/22) of neuropathy, 22% (2/9) of MND and 63% (5/8) of complex phenotypes were given genetic diagnosis. Twenty-seven disease-associated variants were identified including ten novel variants in FBXO38, LAMA2, MFN2, MYH7, PNPLA6, SH3TC2 and SPTLC1. Single-nucleotide variants (n=10) affected conserved residues within functional domains and previously identified mutation hot-spots. Established pathogenic variants (n=16) presented with atypical features, such as optic neuropathy in adult polyglucosan body disease, facial dysmorphism and skeletal anomalies in cerebrotendinous xanthomatosis, steroid-responsive weakness in congenital myasthenia syndrome 10. Potentially treatable rare diseases were diagnosed, improving the quality of life in some patients.ConclusionsIntegrating deep phenotyping, gene filter algorithms and biological assays increased diagnostic yield of exome sequencing, identified novel pathogenic variants and extended phenotypes of difficult to diagnose rare neurogenetic disorders in an outpatient clinic setting.© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

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