Recurrent, founder and hypomorphic variants contribute to shaping the genetic landscape of Joubert syndrome
DOI10.5281/zenodo.6188091Zenodo6188091MaRDI QIDQ6704335FDOQ6704335
Dataset published at Zenodo repository.
Micalizzi Alessia, Valente Enza Maria, Brockmann Knut, Novelli Antonio, Romaniello Romina, Mazzotta Concetta, Gana Simone, Stanzial Franco, Dempsey Jennifer C., Mortarini Giulia, Battini Roberta, Signorini Sabrina, Doherty Dan, Loucks Hailey, D'Abrusco Fulvio, Strisciuglio Pietro, Fischetto Rita, Agolini Emanuele, Bertini Enrico, Serpieri Valentina, Biagini Tommaso, D'Arrigo Stefano, Tommaso Mazza, Borgatti Renato, Nardocci Nardo, Boltshauser Eugen, Romano Alfonso, Palmieri Ilaria
Publication date: 20 February 2022
Copyright license: Creative Commons Attribution 4.0 International
Introduction: This database includes the raw data linked with the paper Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome. In this paper we reported eleven recurrent variants in seven distinct JS genes occurring in our large European JS cohort, including a previously unreported variant in KIAA0586 (c.1006CT). Methods: We evaluated the frequencies of these variants in our cohort of 500 European JS patients and compared them with controls (from three large Italian non-JS cohorts and from the gnomAD database), and with an independent cohort of about 600 JS probands from the United States. Results: All variants were markedly enriched in the European JS cohort compared to all controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazi Jewish founder variant (TMEM216 c.218GT) was significantly enriched in American JS compared to European JS patients, while the MKS1 c.1476TG variant was about ten times more frequent among European JS. Frequencies of all remaining variants were comparable in the two cohorts. Genotyping of several microsatellite markers across the gene loci in carriers of seven variants identified four novel founder haplotypes. Of note, MKS1 c.1476TG was consistently detected in compound heterozygosity with deleterious variants in JS patients, while it was found in homozygosity in an unaffected parent. Functional studies on fibroblasts from this healthy carrier and her affected son showed a similarly reduced percentage of ciliated cells compared to unaffected controls, but much shorter cilia in the patient than in the unaffected homozygous parent, consistent with a hypomorphic effect.
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