title: Exome Sequencing and Gene Prioritization Correct Misdiagnosis in a Chinese Kindred with Familial Amyloid Polyneuropathy.
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.
authors.affiliation: Department of Neurology, Military General Hospital of Beijing PLA, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.|Department of Psychiatry and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Xueya
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Medical Genetics, The Capital Medical University, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: National Research Institute of Family Planning, Beijing, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.
authors.forename: Liyang
authors.initials: L
authors.lastname: Liu
authors.affiliation: National Research Institute of Family Planning, Beijing, China.
authors.forename: Shinan
authors.initials: S
authors.lastname: Wu
authors.affiliation: National Research Institute of Family Planning, Beijing, China.
authors.forename: Tengyan
authors.initials: T
authors.lastname: Li
authors.affiliation: National Research Institute of Family Planning, Beijing, China.
authors.forename: Si
authors.initials: S
authors.lastname: Chen
authors.affiliation: National Research Institute of Family Planning, Beijing, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Psychiatry and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Pak Chung
authors.initials: PC
authors.lastname: Sham
authors.affiliation: Department of Neurology, Military General Hospital of Beijing PLA, Beijing, China.
authors.forename: Guangming
authors.initials: G
authors.lastname: Zhu
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.
authors.forename: Xuegong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: National Research Institute of Family Planning, Beijing, China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Wang
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D028227:Amyloid Neuropathies, Familial / Q000235:genetics*; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D003951:Diagnostic Errors; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011228:Prealbumin / Q000235:genetics*; D012372:ROC Curve; D000073359:Exome Sequencing / Q000379:methods*
chemical_list: D011228:Prealbumin