RT Journal Article
SR Electronic
T1 Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases
JF Journal of Neurology, Neurosurgery & Psychiatry
JO J Neurol Neurosurg Psychiatry
FD BMJ Publishing Group Ltd
SP 1186
OP 1196
DO 10.1136/jnnp-2020-325437
VO 92
IS 11
A1 Grunseich, Christopher
A1 Sarkar, Nathan
A1 Lu, Joyce
A1 Owen, Mallory
A1 Schindler, Alice
A1 Calabresi, Peter A
A1 Sumner, Charlotte J
A1 Roda, Ricardo H
A1 Chaudhry, Vinay
A1 Lloyd, Thomas E
A1 Crawford, Thomas O
A1 Subramony, S H
A1 Oh, Shin J
A1 Richardson, Perry
A1 Tanji, Kurenai
A1 Kwan, Justin Y
A1 Fischbeck, Kenneth H
A1 Mankodi, Ami
YR 2021
UL http://jnnp.bmj.com/content/92/11/1186.abstract
AB Background We 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.Methods WES 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.Results Molecular 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.Conclusions Integrating 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.Data are available on reasonable request.