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PurposeInherited peripheral neuropathies (IPN) represent a large heterogenous group of hereditary diseases with more than 100 causative genes reported to date. In this context, targeted next-generation sequencing (NGS) offers the opportunity to screen all these genes with high efficiency in order to unravel the genetic basis of the disease. Here, we compare the diagnostic yield of targeted NGS with our previous gene by gene Sanger sequencing strategy. We also describe several novel likely pathogenic variants.Design and participantsWe have completed the targeted NGS of 81 IPN genes in a cohort of 123 unrelated patients affected with diverse forms of IPNs, mostly Charcot-Marie-Tooth disease (CMT): 23% CMT1, 52% CMT2, 9% distal hereditary motor neuropathy, 7% hereditary sensory and autonomic neuropathy and 6.5% intermediate CMT.ResultsWe have solved the molecular diagnosis in 49 of 123 patients (~40%). Among the identified variants, 26 variants were already reported in the literature. In our cohort, the most frequently mutated genes are respectively:MFN2,SH3TC2,GDAP1,NEFL,GAN,KIF5AandAARS. Panel-based NGS was more efficient in familial cases than in sporadic cases (diagnostic yield 49%vs19%, respectively). NGS-based search for copy number variations, allowed the identification of three duplications in three patients and raised the diagnostic yield to 41%. This yield is two times higher than the one obtained previously by gene Sanger sequencing screening. The impact of panel-based NGS screening is particularly important for demyelinating CMT (CMT1) subtypes, for which the success rate reached 87% (36% only for axonal CMT2).ConclusionNGS allowed to identify causal mutations in a shorter and cost-effective time. Actually, targeted NGS is a well-suited strategy for efficient molecular diagnosis of IPNs. However, NGS leads to the identification of numerous variants of unknown significance, which interpretation requires interdisciplinary collaborations between molecular geneticists, clinicians and (neuro)pathologists.

AD; International audience; OBJECTIVES: We tested the following hypotheses: (1) risk-averse general practitioners (GPs) might use more Rapid Antigen Diagnostic Tests (RADTs) in tonsillitis in children, probably to decrease their diagnostic uncertainty regarding the aetiology of the disease (viral vs due to group A Streptococcus); and (2) GPs not using RADT might prescribe more antibiotics when they are risk averse. DESIGN, SETTING AND PARTICIPANTS: We conducted a cross-sectional survey of a nationwide French representative sample of 1093 GPs in 2012. OUTCOME MEASURES: Multivariate analyses adjusted on the four stratification variables (age, gender, location and volume of activity, ie, the number of annual consultations) were performed to identify the risk domains associated with indicators of good or poor practice. RESULTS: 69.4% of GPs were aware of national guidelines regarding tonsillitis and declared that they had taken these guidelines into account for their last paediatric tonsillitis case. 59.1% declared they used RADT in their last patient aged between 3 and 16 years presenting with tonsillitis; 29.7% of these tests were positive. Among the GPs who used RADT, 30.7% prescribed an antibiotic; 98.3% did either prescribe an antibiotic because of a positive RADT result, or did not prescribe an antibiotic in view of a negative result. Among the GPs who did not use RADT, 50.7% prescribed an antibiotic. In multivariate analyses, risk-averse GPs declared being more aware of and compliant with guidelines (OR=1.56, p\textless0.01), and used RADTs more often for their last patient (OR=1.30, p\textless0.05). Among GPs not using RADT in their last patient, risk-averse GPs prescribed more antibiotics compared with risk-tolerant doctors (OR=1.18, p\textless0.05). CONCLUSIONS: Individual risk attitudes influenced GPs' practices in tonsillitis, particularly the use of RADTs and antibiotic prescriptions.