The genetic structure of the Turkish population reveals high levels of variation and admixture

The construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes (n = 2,589) or whole genomes (n = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 50% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes

Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis

IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.OBJECTIVE To identify the genetic variants associated with juvenile ALS.DESIGN, SETTING, AND PARTICIPANTS In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.MAIN OUTCOMES AND MEASURES De novo variants present only in the index case and not in unaffected family members.RESULTS Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p. Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.CONCLUSIONS AND RELEVANCE These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.Genetics of disease, diagnosis and treatmen

Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function

The contract in criminal law

En tant que « pilier de l’ordre juridique », le contrat n’est pas ignoré du droit pénal. Incontestablement présent dans d’innombrables incriminations, le contrat fait toutefois l’objet de conceptions particulières que la doctrine relève ponctuellement comme autant de marques d’autonomie de la matière. Mais la présentation du contrat en droit pénal par le simple constat de solutions autonomes ne peut suffire, qui ne permet pas de déterminer, de manière positive et rationnelle, ce en quoi le contrat consiste en droit pénal.En refusant de lui transposer l’ensemble du régime contractuel, le droit positif semble pourtant formuler le principe d’une sélection que la finalité du droit pénal peut éclairer de manière décisive. Le contrat en droit pénal apparaît alors, qui résulte ainsi d’une sélection fonctionnelle des dispositions du régime contractuel : seules celles assurant la finalité du droit pénal doivent être caractérisées.As a « bedrock of the legal order », the contract is not ignored by criminal law. Unquestionably present in many offences, the contract is the object of specific conceptions that the doctrine find here and there as signs of the autonomy of criminal law.However, the presentation of the contract in criminal law through the statement of fact that autonomous solutions exist, is not sufficient. It doesn’t allow establishment in a positive and rational way, the real definition of the contract in criminal law.By refusing transposition of the entire contractual settlement, current law expresses the principle of a selection and that the purpose of criminal law may clarify it in a decisive way.Then, the contract in criminal law appears, resulting of a functional selection from the dispositions of contractual settlement: only the ones which maintain the aim of criminal law must be distinguished

The contract in criminal law

En tant que « pilier de l’ordre juridique », le contrat n’est pas ignoré du droit pénal. Incontestablement présent dans d’innombrables incriminations, le contrat fait toutefois l’objet de conceptions particulières que la doctrine relève ponctuellement comme autant de marques d’autonomie de la matière. Mais la présentation du contrat en droit pénal par le simple constat de solutions autonomes ne peut suffire, qui ne permet pas de déterminer, de manière positive et rationnelle, ce en quoi le contrat consiste en droit pénal.En refusant de lui transposer l’ensemble du régime contractuel, le droit positif semble pourtant formuler le principe d’une sélection que la finalité du droit pénal peut éclairer de manière décisive. Le contrat en droit pénal apparaît alors, qui résulte ainsi d’une sélection fonctionnelle des dispositions du régime contractuel : seules celles assurant la finalité du droit pénal doivent être caractérisées.As a « bedrock of the legal order », the contract is not ignored by criminal law. Unquestionably present in many offences, the contract is the object of specific conceptions that the doctrine find here and there as signs of the autonomy of criminal law.However, the presentation of the contract in criminal law through the statement of fact that autonomous solutions exist, is not sufficient. It doesn’t allow establishment in a positive and rational way, the real definition of the contract in criminal law.By refusing transposition of the entire contractual settlement, current law expresses the principle of a selection and that the purpose of criminal law may clarify it in a decisive way.Then, the contract in criminal law appears, resulting of a functional selection from the dispositions of contractual settlement: only the ones which maintain the aim of criminal law must be distinguished

Alain Rey (auteur), C. Juan Sager (trad. , éd.), préface de Bruno de Bessé (préf.), Essays on Terminology, John Benjamins Publishing Company, Amsterdam-Philadelphie, 1995

Palvadeau Sophie. Alain Rey (auteur), C. Juan Sager (trad. , éd.), préface de Bruno de Bessé (préf.), Essays on Terminology, John Benjamins Publishing Company, Amsterdam-Philadelphie, 1995. In: L'Information Grammaticale, N. 79, 1998. pp. 54-55

Quelques problèms de traduction en français des textes japonais de chimie

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