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Abstract Herein, we report a case of a 73‐year‐old female patient diagnosed with cT4N0M1a lung adenocarcinoma with KRAS G12C mutation, PDL1

Hereditary sensory neuropathies (HSN) are a heterogenous group of sensory neuropathies. Mutations in ATL3 have been described in patients presenting with hereditary sensory neuropathy IF (HSN1F), a subtype of HSN. Herein, by analyzing targeted-NGS data of a patient presenting with sensory neuropathy symptoms using the CovCopCan bioinformatic tool, we discovered the presence of a deletion of around 3kb in ATL3 from Chr11:63,401,422 to Chr11:63,398,182. This deletion affects ATL3 exons 11 and 12 and could lead to the mutation c.(1036-861_1539+329del), p.(Ala346_Gln513del). In addition, an analysis of the breakpoints’ sequences revealed the presence of Alu transposable elements at the position of the breakpoints, which pointed to a possible erroneous recombination event following a non-allelic-homologous-recombination mechanism in this area. Moreover, electronic microscopy analysis of the patient’s nerve biopsy revealed a severe rarefaction of the myelinated fibers, a demyelinating–remyelinating process, and an abnormal aspect of the endoplasmic reticulum. These findings suggest that this structural variation could potentially be responsible for the HSN symptoms of the patient. Research of structural variations in ATL3 in numerous other patients presenting similar symptoms should be broadly investigated in order to improve patients’ diagnoses.

Abstract We describe the clinical, electrodiagnostic, and genetic findings of three homozygous FIG4‐c.122T>C patients suffering from Charcot‐Marie‐Tooth disease type 4J (AR‐CMT‐FIG4). This syndrome usually involves compound heterozygosity associating FIG4‐c.122T>C, a hypomorphic allele coding an unstable FIG4‐p.Ile41Thr protein, and a null allele. While the compound heterozygous patients presenting with early onset usually show rapid progression, the homozygous patients described here show the signs of relative clinical stability. As FIG4 activity is known to be dose dependent, these patients’ observations could suggest that the therapeutic perspective of increasing levels of the protein to improve the phenotype of AR‐CMT‐FIG4‐patients might be efficient.

Next-generation sequencing (NGS) allows the detection of mutations in inherited genetic diseases, like the Charcot-Marie-Tooth disease (CMT) which is the most common hereditary peripheral neuropathy. The majority of mutations detected by NGS are single nucleotide variants (SNVs) or small indels, while structural variants (SVs) are often underdiagnosed. PMP22 was the first gene described as being involved in CMT via a SV of duplication type. To date, more than 90 genes are known to be involved in CMT, with mainly SNVs and short indels described. Herein targeted NGS and the CovCopCan bioinformatic tool were used in two unrelated families, both presenting with typical CMT symptoms with pyramidal involvement. We have discovered two large SVs in KIF5A, a gene known to cause axonal forms of CMT (CMT2) in which no SVs have yet been described. In the first family, the patient presented with a large deletion of 12 kb in KIF5A from Chr12:57,956,278 to Chr12:57,968,335 including exons 2–15, that could lead to mutation c.(130-943_c.1717-533del), p.(Gly44_Leu572del). In the second family, two cases presented with a large deletion of 3 kb in KIF5A from Chr12:57,974,133 to Chr12:57,977,210 including exons 24–28, that could lead to mutation c.(2539-605_*36 + 211del), p.(Leu847_Ser1032delins33). In addition, bioinformatic sequence analysis revealed that a NAHR (Non-Allelic-Homologous-Recombination) mechanism, such as those in the PMP22 duplication, could be responsible for one of the KIF5A SVs and could potentially be present in a number of other patients. This study reveals that large KIF5A deletions can cause CMT2 and highlights the importance of analyzing not only the SNVs but also the SVs during diagnosis of neuropathies.

Context: In Cuba, the venom of the endemic scorpion Rhopalurus junceus has been used in traditional medicine for cancer treatment. The genetic variability in populations from distinct origin and differences in the composition of venom –a little explored topic- could influence the pharmacological effects of products used in medical practice. Aims: To characterize the populations of R. junceus from six different districts of the Moanicum sector in northeastern Cuba, taking into account the variations in the sequences of cytochrome oxidase subunit I gene (COI) and peptide masses of venom. Methods: For the genetic characterization, a 658 bp gene fragment of COI was amplified by PCR. The genetic structure of populations was analyzed hierarchically, using an analysis of molecular variance (AMOVA). In proteomic analysis, molecular masses of venom constituents were arranged in increasing order, and different components were considered when masses differed by 2 Da. Results: R. junceus species in the six districts studied in the Moanicum sector belong to different populations. The sequences of COI gene showed high levels of genetic variability, recovering 47 haplotypes (87% unique). The composition of the venom was also significantly different between the districts. The most abundant components presented masses of 3-6 kDa (K+-channel specific peptides) and 6,1-10 kDa (Na+-channel specific peptides). Conclusions: Populations of R. junceus showed high genetic differentiation and a broad intraspecific variation in the venom peptides (3-10 kDa) in six districts of Moanicum sector of Cuba. This richness in scorpion varieties with different toxins profile should be considered for pharmacological applications.

Next Generation Sequencing (NGS) using capture or amplicons strategies allows the detection of a large number of mutations increasing the rate of positive diagnosis for the patients. However, most of the detected mutations are Single Nucleotide Variants (SNVs) or small indels. Structural Variants (SVs) are often underdiagnosed in inherited genetic diseases, probably because few user-friendly tools are available for biologists or geneticists to identify them easily. We present here the diagnosis of two brothers presenting a demyelinating motor-sensitive neuropathy: a presumed homozygous c.5744_5745delAT in exon 10 of SACS gene was initially detected, while actually these patients were heterozygous for this mutation and harbored a large deletion of SACS exon 10 in the other allele. This hidden mutation has been detected thanks to the user-friendly CovCopCan software. We recommend to systematically use such a software to screen NGS data in order to detect SVs, such as Copy Number Variations, to improve diagnosis of the patients.

CANVAS, a rare disorder responsible for late-onset ataxia of autosomal recessive inheritance, can be misdiagnosed. We investigated a series of eight patients with sensory neuropathy and/or an unexplained cough, who appeared to suffer from CANVAS, and we emphasized the clinical clues for early diagnosis. Investigations included clinical and routine laboratory analyses, skin biopsy, nerve biopsy and molecular genetics. The eight patients had clinical and/or laboratory evidence of sensory neuronopathy. All but one had neuropathic pain that had started in an asymmetric fashion in two patients. A chronic cough was a prominent feature in our eight patients and had started years before neuropathic symptoms in all but one. The course of the disease was slow, and ataxia remained mild in all. Five patients were initially thought to have immune-mediated sensory neuronopathy and received immunotherapy. Skin biopsies showed a near complete and non-length-dependent loss of intraepidermal nerve fibers. Moreover, nerve biopsy findings suggested a prominent involvement of small myelinated and unmyelinated fibers. The burden of CANVAS extends far beyond cerebellar ataxia and vestibular manifestations. Indeed, our study shows that a chronic cough and neuropathic pain may represent a major source of impairment in these patients and should not be overlooked to allow an early diagnosis and prevent unnecessary immunotherapy.

Abstract Background With an ever-growing number of published genomes, many low levels of the Tree of Life now contain several species with enough molecular data to perform shallow-scale phylogenomic studies. Moving away from using just a few universal phylogenetic markers, we can now target thousands of other loci to decipher taxa relationships. Making the best possible selection of informative sequences regarding the taxa studied has emerged as a new issue. Here, we developed a general procedure to mine genomic data, looking for orthologous single-copy loci capable of deciphering phylogenetic relationships below the generic rank. To develop our strategy, we chose the genus Rosa, a rapid-evolving lineage of the Rosaceae family in which several species genomes have recently been sequenced. We also compared our loci to conventional plastid markers, commonly used for phylogenetic inference in this genus. Results We generated 1856 sequence tags in putative single-copy orthologous nuclear loci. Associated in silico primer pairs can potentially amplify fragments able to resolve a wide range of speciation events within the genus Rosa. Analysis of parsimony-informative site content showed the value of non-coding genomic regions to obtain variable sequences despite the fact that they may be more difficult to target in less related species. Dozens of nuclear loci outperform the conventional plastid phylogenetic markers in terms of phylogenetic informativeness, for both recent and ancient evolutionary divergences. However, conflicting phylogenetic signals were found between nuclear gene tree topologies and the species-tree topology, shedding light on the many patterns of hybridization and/or incomplete lineage sorting that occur in the genus Rosa. Conclusions With recently published genome sequence data, we developed a set of single-copy orthologous nuclear loci to resolve species-level phylogenomics in the genus Rosa. This genome-wide scale dataset contains hundreds of highly variable loci which phylogenetic interest was assessed in terms of phylogenetic informativeness and topological conflict. Our target identification procedure can easily be reproduced to identify new highly informative loci for other taxonomic groups and ranks.

Next generation sequencing (NGS) is strategically used for genetic diagnosis in patients with Charcot–Marie–Tooth disease (CMT) and related disorders called non-syndromic inherited peripheral neuropathies (NSIPN) in this paper. With over 100 different CMT-associated genes involved and ongoing discoveries, an important interlaboratory diversity of gene panels exists at national and international levels. Here, we present the work of the French National Network for Rare Neuromuscular Diseases (FILNEMUS) genetic diagnosis section which coordinates the seven French diagnosis laboratories using NGS for peripheral neuropathies. This work aimed to establish a unique, simple and accurate gene classification based on literature evidence. In NSIPN, three subgroups were usually distinguished: (1) HMSN, Hereditary Motor Sensory Neuropathy, (2) dHMN, distal Hereditary Motor Neuropathy, and (3) HSAN, Hereditary Sensory Autonomic Neuropathy. First, we reported ClinGen evaluation, and second, for the genes not evaluated yet by ClinGen, we classified them as “definitive” if reported in at least two clinical publications and associated with one report of functional evidence, or “limited” otherwise. In total, we report a unique consensus gene list for NSIPN including the three subgroups with 93 genes definitive and 34 limited, which is a good rate for our gene’s panel for molecular diagnostic use.

Next-generation sequencing (NGS) allows the detection of plentiful mutations increasing the rate of patients getting a positive diagnosis. However, while single-nucleotide variants (SNVs) or small indels can be easily detected, structural variations (SVs) such as copy number variants (CNVs) are often not researched. In Charcot–Marie–Tooth disease (CMT), the most common hereditary peripheral neuropathy, the PMP22-duplication was the first variation detected. Since then, more than 90 other genes have been associated with CMT, with point mutations or small indels mostly described. Herein, we present a personalized approach we performed to obtain a positive diagnosis of a patient suffering from demyelinating CMT. His NGS data were aligned to the human reference sequence but also studied using the CovCopCan software, designed to detect large CNVs. This approach allowed the detection of only one mutation in SH3TC2, the frequent p.Arg954*, while SH3TC2 is known to be responsible for autosomal recessive demyelinating CMT forms. Interestingly, by modifying the standard CovCopCan use, we detected the second mutation of this patient corresponding to a 922 bp deletion in SH3TC2 (Chr5:148,390,609-Chr5:148,389,687), including only one exon (exon 14). This highlights that SVs, different from PMP22 duplication, can be responsible for peripheral neuropathy and should be searched systematically. This approach could also be employed to improve the diagnosis of all inherited diseases.

La littérature contemporaine de l’océan Indien, et de l’île Maurice en particulier, livre des portraits marquants de femmes violentes et/ou criminelles. Cette violence est d’autant plus saisissante qu’elle émane d’espaces post-esclavagistes et postcoloniaux dans lesquels les femmes ont été victimisées et leurs corps réifiés. Peut-elle être lue comme une reprise de pouvoir paradoxale qui déferait les assignations de genres et troublerait l’ordre des dominations ? Considérer la violence ou le crime commis par des femmes comme simplement réactionnels risquerait toutefois d’aboutir à une dépolitisation de leur acte. La littérature contemporaine, en insistant sur une intersectionnalité des rapports de classes, de couleurs, d’âges, met en exergue la colère qui gronde chez ces femmes. Le crime peut-il être l’une de ces « tactiques » qui consistent à trouver une place pour soi dans un lieu imposé et configuré par l’autre, voire comme une stratégie politique qui aiderait à la constitution d’un nouveau langage pour dire les mondes postcoloniaux ? Nous nous posons ces questions à propos de deux romans mauriciens, Le Journal d’une vieille folle d’Umar Timol et Blue Bay Palace de Nathacha Appanah. Mots-clés : Ile Maurice, violence féminine, crime, pouvoir, intersectionnalité, stratégie

BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in NPM1c AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was TP53 independent in the NPM1c cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of NPM1c cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in NPM1c IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a NPM1c specific HOX gene signature while anti-leukemic effects of BETi appear HOX gene independent. Our preclinical results encourage clinical testing of BETi in NPM1c AML patients.