Inherited neuropathies show considerable heterogeneity in medical manifestations and genetic etiologies, and are therefore often hard to diagnose. conditions, including sensory, engine, and autonomic neuropathies. The most common type is definitely Charcot-Marie-Tooth (CMT), or hereditary engine and sensory neuropathies1. The medical classification is hard due to overlapping symptoms, and it requires insensitive evaluations by experienced neurologists2, which may Pracinostat not constantly be practical in routine clinics3. Neuropathy can also be part of more generalized multisystem syndrome1, adding difficulty Pracinostat to phenotype evaluation. It is therefore of interest to identify molecular genetic causes, which allows for prognosis, aids the family planning, or even suggests customized treatment. However, genetic analysis of inherited neuropathy was traditionally hindered by its genetic heterogeneity, with at least 80 disease genes recognized so much1,4. Whole exome sequencing (WES) has now been widely used in molecular analysis of Mendelian disorders5,6, and has been shown to resolve undiagnosed conditions7 and to save misdiagnosis in some Pracinostat cases8. The ability to survey the entire protein coding region of the genome makes WES ideally suitable for disease like inherited neuropathy, which shows locus heterogeneity and wide phenotype spectrum9,10,11,12. Rapidly narrowing down the scope of disease-causing mutations is the key to make a timely genetic analysis13. Recent large-scale investigations typically used a combination of disease-specific knowledgebase14, inheritance mode15, and bioinformatics prediction of deleteriousness16. They also showed the diagnostic yield for autosomal dominating cases was lower than normal16,17,18, partly because of the difficulty in sifting through large number of private variants especially when only one solitary patient was sequenced. Computational Goat polyclonal to IgG (H+L)(HRPO) methods for gene prioritization have undergone continuous development19; but their energy in analyzing medical WES data remained to be demonstrated. In the present study, we investigated the genetic cause of polyneuropathy within a large Chinese kindred ascertained from a patient in the beginning diagnosed as CMT disease. After excluding the causes of known CMT genes, we performed WES in one patient and applied computational prioritization to rank rare functional variants. We report the use of this approach to save the initial misdiagnosis in the proband and suggest new treatment options to the individuals. Results Clinical Summary The proband (III:21) was a 44-year-old man, showing with distributing progressive limbs weakness and paresthesia. The patient in the beginning experienced slight weakness in lower limbs after labor work ten years before admission to clinic. Five years ago, he started to experienced temp loss and numbness in his right middle toe, which gradually progressed to knee bones and hands inside a symmetrical fashion. Intermittent diarrhea without abdominal pain or vomiting occurred three years ago followed by severe weight loss, but no abnormality was found by colonoscopy exam. Around the same time, he started to develop severe weakness in limbs and was no longer proficient for physical labor. Two years ago, he offered frequent syncope which occurred mostly at standing up position. Urinary and fecal incontinence, were also noticed shortly. In physical exam, right and bilateral foot drop were observed. Blood pressure (BP) measurements exposed orthostatic hypotension (systolic/diastolic BP: 115/68?mmHg in recumbent and 50/30?mmHg in standing up position). Neurological exam showed slight muscle mass weakness (5-/4, MRC level) in the top and lower extremities with muscular atrophy (Fig. 1A). Abdominal, cremasteric, plantar, and Pracinostat deep tendon reflexes were all absent. Sensory exam showed severe loss of pin-prick, temp, and light-touch understanding mainly in the distal part of four extremities. Vibration and position senses were also impaired. Number 1 Clinical and pathological features of the proband. Nerve condition studies (Supplementary Table S1) shown that the velocity and compound muscle mass action potential (CMAP) of bilateral tibial nerve and common peroneal nerve could not be elicited. Similarly, sensory conduction velocity and sensory nerve action potential (SNAP) of tibial, sural, and common peroneal nerves in the lower limbs could also not become recognized. Both CMAP and SNAP of median and ulnar nerves showed decreased amplitudes and long term distal latency. Electromyogram exam showed neurogenic damage in the 1st dorsal interosseous muscle mass and remaining tibial anterior muscle mass. Echocardiography exam showed remaining ventricular hypertrophy, diffuse thickening of the remaining ventricular wall, and decreased diastolic function of the remaining.