[Genetics of amyotrophic lateral sclerosis]. / Génétique de la sclérose latérale amyotrophique.

GENETICS OF AMYOTROPHIC LATERAL SCLEROSIS. Approximately 10 to 15% of people with amyotrophic lateral sclerosis (ALS) have a family history of the disease. In 2/3 of them, but also in 10% of subjects without any family history of ALS, a pathogenic genetic variant can be identified. Many genes are involved, the four main ones being C9orf72 (which can also be responsible for dementia), SOD1, TARDBP and FUS. ALS of genetic origin is almost always inherited in an autosomal dominant pattern. The progress made in recent years in the knowledge of the genetic forms of ALS has led to a better understanding of the pathophysiology of the disease and has opened up new therapeutic avenues, some of which are already being explored. For all these reasons, it is now recommended that all patients with ALS, whether familial or not, undergo a genetic investigation, with analyses appropriate to their age and family history. When a pathogenic variant is found, it can then be sought in at-risk relatives who so desire. These tests must follow legally mandated procedures and can only be conducted in a specialized ALS center under the supervision of a geneticist after a thorough discussion of the personal and family implications of the result and written consent from the patient.

GÉNÉTIQUE DE LA SCLÉROSE LATÉRALE AMYOTROPHIQUE. Environ 10 à 15 % des sujets atteints de sclérose latérale amyotrophique (SLA) ont des antécédents familiaux. Chez les deux tiers d'entre eux, mais aussi chez 10 % des sujets sans aucun antécédent familial de SLA, un variant génétique pathogène peut être mis en évidence. De nombreux gènes sont concernés, les quatre principaux étant C9orf72 (qui peut également être responsable d'une démence), SOD1, TARDBP et FUS . La SLA d'origine génétique se transmet pratiquement toujours selon une hérédité autosomique dominante. Les progrès accomplis ces dernières années dans la connaissance des formes génétiques de SLA permettent de mieux connaître la physiopathologie de la maladie et ouvrent de nouvelles pistes thérapeutiques dont certaines sont déjà en cours d'exploration. Pour toutes ces raisons, il est aujourd'hui recommandé, chez tout sujet atteint de SLA, familiale ou non, d'entreprendre une enquête génétique, avec des analyses appropriées à l'âge et aux antécédents familiaux. Lorsqu'un variant pathogène est trouvé, il peut alors être recherché chez les apparentés à risque qui le souhaitent. Ces analyses doivent respecter des procédures encadrées par la loi, et ne peuvent être conduites que dans un centre spécialisé pour la prise en charge de la SLA, et sous la responsabilité d'un généticien, après une discussion approfondie sur les implications personnelles et familiales du résultat, et le consentement écrit du patient.

POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies.

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.

Mapping disease incidence in suburban areas using remotely sensed data.

A method using remotely sensed data was developed to map the incidence of Q fever in the vicinity of Cayenne, French Guiana. A satellite image was processed to map land cover and generate a population density index, which was used to determine areas of high disease incidence during the 1996-2000 period. A comparison with results obtained using population census data showed strong concordance between the two incidence maps. All high-incidence areas identified using population census data were also detected using remotely sensed data. This demonstrates the potential of remote sensing as a new tool for rapid mapping of disease incidence in epidemiologic surveys.