With the advent of whole exome sequencing, cases where no pathogenic coding mutations can be found are increasingly being observed in many diseases. In two large, distantly-related families that mapped to the Charcot-Marie-Tooth neuropathy CMTX3 locus at chromosome Xq26.3-q27.3, all coding mutations were excluded. Using whole genome sequencing we found a large DNA interchromosomal insertion within the CMTX3 locus. The 78 kb insertion originates from chromosome 8q24.3, segregates fully with the disease in the two families, and is absent from the general population as well as 627 neurologically normal chromosomes from in-house controls. Large insertions into chromosome Xq27.1 are known to cause a range of diseases and this is the first neuropathy phenotype caused by an interchromosomal insertion at this locus. The CMTX3 insertion represents an understudied pathogenic structural variation mechanism for inherited peripheral neuropathies. Our finding highlights the importance of considering all structural variation types when studying unsolved inherited peripheral neuropathy cases with no pathogenic coding mutations.
BackgroundSoil-transmitted helminths (STHs) including Ascaris lumbricoides, Necator americanus, Ancylostoma spp. and Trichuris trichiura are cause of significant global morbidity. To mitigate their disease burden, at-risk groups in endemic regions receive periodic mass drug administration using anthelmintics, most commonly albendazole and mebendazole. Assessing the efficacy of anthelmintic drugs is important for confirming that these regimens are working effectively and that drug resistance has not emerged. In this study we aimed to characterise the therapeutic efficacy of albendazole against Ascaris spp. and N. americanus in Timor-Leste, using a quantitative polymerase chain reaction (qPCR) method for parasite detection and quantification.ResultsA total of 314 participants from 8 communities in Timor-Leste provided stool samples before and 10–14 days after the administration of a single 400 mg dose of albendazole. Helminth infection status and infection intensity (measured in Ct-values and relative fluorescence units) were determined using qPCR. Efficacy was determined by examining the cure rates and infection intensity reduction rates. Albendazole was found to be highly efficacious against Ascaris spp., with a cure rate of 91.4% (95% CI: 85.9–95.2%) and infection intensity reduction rate of 95.6% (95% CI: 88.3–100%). The drug was less efficacious against N. americanus with a cure rate of 58.3% (95% CI: 51.4–64.9%) and infection intensity reduction rate of 88.9% (95% CI: 84.0–97.0%).ConclusionsThe observed cure rates and infection intensity reduction rates obtained for Ascaris spp. and to a lower extent N. americanus, demonstrate the continued efficacy of albendazole against these species and its utility as a mass chemotherapy agent in Timor-Leste. Furthermore, this study demonstrates the usefulness of qPCR as a method to measure the efficacy of anthelminthic drugs. Additional research is necessary to translate Ct-values into eggs per gram in a systematic way.Trial registrationAustralian and New Zealand Clinical Trials Registry 12614000680662 (registered 27 June 2014).
BackgroundRelapsing polychondritis (RP) is a rare systemic disease, characterised by recurrent episodes of inflammation of cartilaginous tissues and other proteoglycan rich structures involving the cartilage of the ears, nose, larynx, tracheobronchial tree and cardiovascular system.1 2 The susceptibility to RP has been reported to be significantly related to genetic factors.3 4 However, family occurrence has yet to be reported and the responsible molecular genetic determinants hasn’t been clearly elucidated.ObjectivesThe purpose was to detect the susceptibility genes of RP through whole-exome sequencing (WES) in a Chinese family and deepen our understanding of the pathogenesis of RP.MethodsA 32 year-old Chinese female proband with RP and her family in which only her mother was RP patient were recruited in the current study. The genomic DNA of 6 human subjects was extracted from the peripheral blood monocyte cells (PBMCs) and then identified gene allele mutations using WES. Candidate variants with low frequency (<0.1%) in general population and predicted deleterious on gene function were identified. Sanger sequencing was then used to validate the analysis results of WES and further validated the gene variants in 12 human subjects.Results38 genes mutated were confirmed by WES among RP patients. Of them, 10 gene mutated were validated by Sanger sequencing, including Collagen Type XXII Alpha 1 Chain (COL22A1) rs200464636, folliculin (FLCN) NM_144606: c.G838A: p.E280K, glycosylphosphatidylinositol anchor attachment 1 (GPAA1) rs201424010, DNA ligase 3 (LIG3) rs761808558, RecQ like helicase 4 (RECQL4) rs757703895, ring finger protein 207 (RNF207) NM_207396: c.T425C:p.I142T, coiled-coil domain containing 61 (CCDC61) rs777816675, Purkinje cell protein 2 (PCP2) rs144974437, tubulin alpha 3e (TUBA3E) rs749780020 and myosin heavy chain 15 (MYH15) NM_014981: c.G4462A: p.A1488T.ConclusionsThis study confirms that coinheritance of multigene mutated may contribute to the susceptibility to RP. The candidate genes mutated we discovered are potential targets for in-depth functional studies.References[1] McAdam LP, O’Hanlan MA, Bleustone R, Pearson CM. Relapsing polychondritis: prospective study of 23 patients and review of the literature. Medicine (Baltimore)1976;55:193–215.[2] Trentham DE, Le CH. Relapsing polychondritis. Ann Intern Med1998;129:114–122.[3] Lang B, Rothenfusser A, Lanchbury JS, Rauh G, Breedveld FC, Urlacher A, Albert ED, Peter HH, Melchers I. Susceptibility to relapsing polychondritis is associated with HLA-DR4.Arthritis Rheum1993;36(5):660–664.[4] Zeuner M, Straub RH, Rauh G, Albert ED, Scholmerich J, Lang B. Relapsing polychondritis: clinical and immunogenetic analysis of 62 patients. J Rheumatol1997;24(1):96–101.AcknowledgementsThis study was supported by Guangdong Natural Science Funds for Distinguished Young Scholar (Grant No. 2014A030306039), High-level personnel of special support program for Technology Innovative Talents and the Top Young of Guangdong Province (Grant No.2015TQ01R516), Distinguished Young Sc...
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