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Effectiveness of clinical exome sequencing in adult patients with difficult‐to‐diagnose neurological disorders
Author(s) -
Sainio Markus T.,
Aaltio Juho,
Hyttinen Virva,
Kortelainen Mika,
Ojanen Simo,
Paetau Anders,
Tienari Pentti,
Ylikallio Emil,
Auranen Mari,
Tyynismaa Henna
Publication year - 2022
Publication title -
acta neurologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.967
H-Index - 95
eISSN - 1600-0404
pISSN - 0001-6314
DOI - 10.1111/ane.13522
Subject(s) - exome sequencing , medicine , genetic testing , ataxia , parkinsonism , pediatrics , hereditary spastic paraplegia , genetic counseling , bioinformatics , genetics , mutation , phenotype , biology , psychiatry , gene , disease
Objectives Clinical diagnostics in adults with hereditary neurological diseases is complicated by clinical and genetic heterogeneity, as well as lifestyle effects. Here, we evaluate the effectiveness of exome sequencing and clinical costs in our difficult‐to‐diagnose adult patient cohort. Additionally, we expand the phenotypic and genetic spectrum of hereditary neurological disorders in Finland. Methods We performed clinical exome sequencing (CES) to 100 adult patients from Finland with neurological symptoms of suspected genetic cause. The patients were classified as myopathy ( n = 57), peripheral neuropathy ( n = 16), ataxia ( n = 15), spastic paraplegia ( n = 4), Parkinsonism ( n = 3), and mixed ( n = 5). In addition, we gathered the costs of prior diagnostic work‐up to retrospectively assess the cost‐effectiveness of CES as a first‐line diagnostic tool. Results The overall diagnostic yield of CES was 27%. Pathogenic variants were found for 14 patients (in genes ANO5 , CHCHD10 , CLCN1 , DES , DOK7 , FKBP14 , POLG , PYROXD1 , SCN4A , TUBB3 , and TTN ) and likely pathogenic previously undescribed variants for 13 patients (in genes ABCD1 , AFG3L2 , ATL1 , CACNA1A , COL6A1 , DYSF , IRF2BPL , KCNA1 , MT ‐ ATP6 , SAMD9L , SGCB , and TPM2 ). Age of onset below 40 years increased the probability of finding a genetic cause. Our cost evaluation of prior diagnostic work‐up suggested that early CES would be cost‐effective in this patient group, in which diagnostic costs increase linearly with prolonged investigations. Conclusions Based on our results, CES is a cost‐effective, powerful first‐line diagnostic tool in establishing the molecular diagnosis in adult neurological patients with variable symptoms. Importantly, CES can markedly shorten the diagnostic odysseys of about one third of patients.