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Large-scale next-generation sequencing (NGS) germline testing is technically feasible today, but variant interpretation represents a major bottleneck in analysis workflows. This includes extensive variant prioritization, annotation, and time-consuming evidence curation. The scale of the interpretation problem is massive, and variants of uncertain significance (VUSs) are a challenge to personalized medicine. This challenge is further compounded by the complexity and heterogeneity of the standards used to describe genetic variants and the associated phenotypes when searching for relevant information to support clinical decision making. To address this, all five Swiss academic institutions for Medical Genetics joined forces with the Swiss Institute of Bioinformatics (SIB) to create SwissGenVar as a user-friendly nationwide repository and sharing platform for genetic variant data generated during routine diagnostic procedures and research sequencing projects. Its aim is to provide a protected environment for expert evidence sharing about individual variants to harmonize and upscale their significance interpretation at the clinical grade according to international standards. To corroborate the clinical assessment, the variant-related data will be combined with consented high-quality clinical information. Broader visibility will be achieved by interfacing with international databases, thus supporting global initiatives in personalized healthcare.

Primary congenital hydrocephalus (PCH) is characterized by ventriculomegaly, defined as a dilation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. PCH, highly heterogenous in etiology, affects 1 in 1,000 live births, where its poor prognosis and lack of satisfactory treatments, underscores our incomplete understanding of PCH pathogenesis. While epidemiological data suggest an underlying genetic cause in up to 40% of congenital hydrocephalus cases, few genes have been discovered as causal of PCH where ventriculomegaly is the sole or primary clinical feature.The work presented within this thesis represents the study through whole-exome sequencing (WES) of a cohort of 28 inbred/outbred families with PCH. Analysis for rare transmitted or de novo mutations (MAF <0.005) uncovered novel mutations in known genes associated with PCH (POMT2, POMGNT1, CRADD, ARID1A and KIDINS220), thus broadening the spectrum of known mutations in PCH. In a consanguineous family we identified a mutation in KIDINS220 shared among the three fetuses presenting brain ventriculomegaly and limb contractures, a gene previously reported in one family with an identical phenotype. Through immunoprecipitation experiments, we showed that the mutation diminished the interaction of KIDINS220 with TrkA, a receptor important in cell survival signaling.In three PCH probands, we identified variants in three potential candidate genes, which reflect the heterogenous genetic landscape of PCH as they are involved in minor spliceosome (RNPC3), angiogenesis (TIE1) and ciliary structure (DNAH2). Though literature poses these genes as strong candidates, further investigation will be required to ascertain them as such.With the increasing number of reports demonstrating that disorders traditionally considered as monogenic are in fact caused by a combination of mutant genes, possible oligogenic inheritance of human PCH was investigated. As ciliary defects of motile and more, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

Background Renal operational tolerance is a rare and beneficial state of prolonged renal allograft function in the absence of immunosuppression. The underlying mechanisms are unknown. We hypothesized that tolerance might be driven by inherited protein coding genetic variants with large effect, at least in some patients. Methods We set up a European survey of over 218,000 renal transplant recipients and collected DNAs from 40 transplant recipients who maintained good allograft function without immunosuppression for at least 1 year. We performed an exome-wide association study comparing the distribution of moderate to high impact variants in 36 tolerant patients, selected for genetic homogeneity using principal component analysis, and 192 controls, using an optimal sequence-kernel association test adjusted for small samples. Results We identified rare variants of HOMER2 (3/36, FDR 0.0387), IQCH (5/36, FDR 0.0362), and LCN2 (3/36, FDR 0.102) in 10 tolerant patients vs .0 controls. One patient carried a variant in both HOMER2 and LCN2 .Furthermore, the three genes showed an identical variant in two patients each. The three genes are expressed at the primary cilium, a key structure in immune responses. Conclusion Rare protein coding variants are associated with operational tolerance in a sizable portion of patients. Our findings have important implications for a better understanding of immune tolerance in transplantation and other fields of medicine. ClinicalTrials.gov ,identifier: NCT05124444., SCOPUS: ar.j, info:eu-repo/semantics/published

Observational population studies indicate that prevention of dementia and cognitive decline is being accomplished, possibly as an unintended result of better vascular prevention and healthier lifestyles. Population aging in the coming decades requires deliberate efforts to further decrease its prevalence and societal burden. Increasing evidence supports the efficacy of preventive interventions on persons with intact cognition and high dementia risk. We report recommendations for the deployment of second-generation memory clinics (Brain Health Services) whose mission is evidence-based and ethical dementia prevention in at-risk individuals. The cornerstone interventions consist of (i) assessment of genetic and potentially modifiable risk factors including brain pathology, and risk stratification, (ii) risk communication with ad-hoc protocols, (iii) risk reduction with multi-domain interventions, and (iv) cognitive enhancement with cognitive and physical training. A roadmap is proposed for concept validation and ensuing clinical deployment.

Bi-allelic variants affecting one of the four genes encoding the AP4 subunits are responsible for the “AP4 deficiency syndrome.” Core features include hypotonia that progresses to hypertonia and spastic paraplegia, intellectual disability, postnatal microcephaly, epilepsy, and neuroimaging features. Namely, AP4M1 (SPG50) is involved in autosomal recessive spastic paraplegia 50 (MIM, SCOPUS: ar.j, info:eu-repo/semantics/published

Large-scale next-generation sequencing (NGS) germline testing is technically feasible today, but variant interpretation represents a major bottleneck in analysis workflows including the extensive variant prioritization, annotation, and time-consuming evidence curation. The scale of the interpretation problem is massive, and variants of uncertain significance (VUS) are a challenge to personalized medicine. This challenge is further compounded by the complexity and heterogeneity of standards used to describe genetic variants and associated phenotypes when searching for relevant information to inform clinical decision-making. For this purpose, all five Swiss academic Medical Genetics Institutions joined forces with the Swiss Institute of Bioinformatics (SIB) to create SwissGenVar as a user-friendly nationwide repository and sharing platform for genetic variant data generated during routine diagnostic procedures and research sequencing projects. Its objective is to provide a protected environment for expert evidence sharing about individual variants to harmonize and up-scale their significance interpretation at clinical grade following international standards. To corroborate the clinical assessment, the variant-related data are combined with consented high-quality clinical information. Broader visibility will be gained by interfacing with international databases, thus supporting global initiatives in personalized health care.

Le développement et l’évolution du cerveau humain sont depuis longtemps des sujets d’études fascinants, et d’autant plus depuis quelques années par l’avancée des données génomiques, transcriptomiques, et des modèles d’études disponibles. Durant ce projet, je me suis focalisée sur CROCCP2, un gène spécifique à la lignée des hominidés qui est apparu durant l’évolution a partir d’une duplication partielle du gène ancestral CROCC (Ciliary Rootlet Coiled Coil), aussi appelé rootletin. CROCC est le composant majeur du ciliary rootlet, un organelle dont le role est encore très mal connu, situé a la base du cil primaire. Au cours de cette étude nous avons découvert que CROCCP2 est exprimé fortement au cours du développement cortical humain mais pas au cours du développement cortical des autres primates. Le gain de fonction de CROCCP2 au cours de la corticogenèse murine in vivo est associé avec une réduction de la ciliogenèse, une hyper-activation de la voie mTOR, et une augmentation de la taille des cellules de glie radiaire, qui ont pour conséquence une amplification des progéniteurs corticaux et de la neurogenèse. L’action de CROCCP2 sur la dynamique ciliaire et la neurogenèse implique l’inhibition de IFT20, une protéine impliquée dans le transport ciliaire. De plus nous avons obtenu des données préliminaires suggérant que CROCCP2 est actif au cours de la corticogenèse humaine.En conclusion nous avons identifié une protéine présente dans le cortex humain ayant un rôle majeur dans l’expansion des progéniteurs corticaux via la modulation de la dynamique ciliaire ., Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished