A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement.
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Prasad Megana K, Geoffroy Véronique, Vicaire Serge, Jost Bernard, Dumas Michael, Le Gras Stéphanie, Switala Marzena, Gasse Barbara, Laugel-Haushalter Virginie, Paschaki Marie, Leheup Bruno, Droz Dominique, Dalstein Amelie, Loing Adeline, Grollemund Bruno, Muller-Bolla Michèle, Lopez-Cazaux Séréna, Minoux Maryline, Jung Sophie, Obry Frédéric, Vogt Vincent, Davideau Jean-Luc, Davit-Beal Tiphaine, Kaiser Anne-Sophie, Moog Ute, Richard Béatrice, Morrier Jean-Jacques, Duprez Jean-Pierre, Odent Sylvie, Bailleul-Forestier Isabelle, Rousset Monique Marie, Merametdijan Laure, Toutain Annick, Joseph Clara, Giuliano Fabienne, Dahlet Jean-Christophe, Courval Aymeric, El Alloussi Mustapha, Laouina Samir, Soskin Sylvie, Guffon Nathalie, Dieux Anne, Doray Bérénice, Feierabend Stephanie, Ginglinger Emmanuelle, Fournier Benjamin, de la Dure Molla Muriel, Alembik Yves, Tardieu Corinne, Clauss François, Berdal Ariane, Stoetzel Corinne, Manière Marie Cécile, Dollfus Hélène, Bloch-Zupan Agnès
Аннотация
METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption.
RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases.
CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease.
TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824.