Abstract
Inherited neuropathies show considerable heterogeneity in clinical manifestations and genetic etiologies, and are therefore often difficult to diagnose. Whole-exome sequencing (WES) has been widely adopted to make definite diagnosis of unclear conditions, with proven efficacy in optimizing patients’ management. In this study, a large Chinese kindred segregating autosomal dominant polyneuropathy with incomplete penetrance was ascertained through a patient who was initially diagnosed as Charcot-Marie-Tooth disease. To investigate the genetic cause, forty-six living family members were genotyped by SNP microarrays, and one confirmed patient was subject to WES. Through systematic computational prioritization, we identified a missense mutation c.G148T in TTR gene which results in a p.V50L substitution known to cause transthyretin-related familial amyloid polyneuropathy. Co-segregation analysis and clinical follow-up confirmed the new diagnosis, which suggested new therapeutic options to the patients and informed high risk family members. This study confirms WES as a powerful tool in translational medicine, and further demostrates the practical utility of gene prioritization in narrowing the scope of causative mutation.
Highlights
Inherited neuropathies are a group of related disorders with debilitating conditions, including sensory, motor, and autonomic neuropathies
We investigated the genetic cause of polyneuropathy within a large Chinese kindred ascertained from a patient initially diagnosed as CMT disease
We report the use of this approach to rescue the initial misdiagnosis in the proband and suggest new treatment options to the patients
Summary
Inherited neuropathies are a group of related disorders with debilitating conditions, including sensory, motor, and autonomic neuropathies. Recent large-scale investigations typically used a combination of disease-specific knowledgebase[14], inheritance mode[15], and bioinformatics prediction of deleteriousness[16]. They showed that the diagnostic yield for autosomal dominant cases was lower than average[16,17,18], partly because of the difficulty in sifting through large number of private variants especially www.nature.com/scientificreports/. We investigated the genetic cause of polyneuropathy within a large Chinese kindred ascertained from a patient initially diagnosed as CMT disease. After excluding the causes of known CMT genes, we performed WES in a single patient and applied computational prioritization to rank rare functional variants. We report the use of this approach to rescue the initial misdiagnosis in the proband and suggest new treatment options to the patients
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