Browsing by Author "Casanova, J.-L."

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Open Access
The genetic structure of the Turkish population reveals high levels of variation and admixture
(National Academy of Sciences, 2020-12-18) Kars, Meltem Ece; Başak, A. N.; Onat, Onur Emre; Bilguvar, K.; Choi, J.; Itan, Y.; Çağlar, C.; Palvadeau, R.; Casanova, J.-L.; Cooper, D. N.; Stenson, P. D.; Yavuz, A.; Buluş, H.; Günel, M.; Friedman, J. M.; Özçelik, Tayfun
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 30% 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.
Open Access
A global effort to define the human genetics of protective immunity to SARS-CoV-2 infection
(Elsevier, 2020) Casanova, J.-L.; Su, H. C.; Abel, L.; Aiuti, A.; Almuhsen, S.; Arias, A. A.; Bastard, P.; Biggs, C.; Bogunovic, D.; Boisson, B.; Boisson-Dupuis, S.; Bolze, A.; Bondarenko, A.; Bousfiha, A.; Brodin, P.; Bustamante, J.; Butte, M.; Casari, G.; Ciancanelli, M.; Cobat, A.; Condino-Neto, A.; Cooper, M.; Dalgard, C.; Espinosa, S.; Feldman, H.; Fellay, J.; Franco, J. L.; Hagin, D.; Itan, Y.; Jouanguy, E.; Lucas, C.; Mansouri, D.; Meyts, I.; Milner, J.; Mogensen, T.; Morio, T.; Ng, L.; Notarangelo, L. D.; Okada, S.; Özçelik, Tayfun; Palacín, P. S.; Planas, A.; Prando, C.; Puel, A.; Pujol, A.; Redin, C.; Renia, L.; Gallego, J. C. R.; Quintana-Murci, L.; Sancho-Shimizu, V.; Sankaran, V.; Seppänen, M. R. J.; Shahrooei, M.; Snow, A.; Spaan, A.; Tangye, S.; Tur, J. P.; Turvey, S.; Vinh, D. C.; von Bernuth, H.; Wang, X.; Zawadzki, P.; Zhang, Q.; Zhang, S.
SARS-CoV-2 infection displays immense inter-individual clinical variability, ranging from silent infection to lethal disease. The role of human genetics in determining clinical response to the virus remains unclear. Studies of outliers—individuals remaining uninfected despite viral exposure and healthy young patients with life-threatening disease—present a unique opportunity to reveal human genetic determinants of infection and disease.
Open Access
SARS-CoV-2–related MIS-C: A key to the viral and genetic causes of Kawasaki disease?
(Rockefeller University Press, 2021) Sancho-Shimizu, V.; Brodin, P.; Cobat, A.; Biggs, C. M.; Toubiana, J.; Lucas, C. L.; Henrickson, S. E.; Belot, A.; MIS-C@CHGE; Tangye, S. G.; D. Milner, J.; Levin, M.; Abel, L.; Bogunovic, D.; Casanova, J.-L.; Zhang, S. -Y.; Özçelik, Tayfun
Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.