AUTHOR=Bloch-Zupan Agnes , Rey Tristan , Jimenez-Armijo Alexandra , Kawczynski Marzena , Kharouf Naji , O-Rare consortium , Dure-Molla Muriel de La , Noirrit Emmanuelle , Hernandez Magali , Joseph-Beaudin Clara , Lopez Serena , Tardieu Corinne , Thivichon-Prince Béatrice , ERN Cranio Consortium , Dostalova Tatjana , Macek Milan , International Consortium , Alloussi Mustapha El , Qebibo Leila , Morkmued Supawich , Pungchanchaikul Patimaporn , Orellana Blanca Urzúa , Manière Marie-Cécile , Gérard Bénédicte , Bugueno Isaac Maximiliano , Laugel-Haushalter Virginie , Alembik Yves , Ahossi Victorin , Bailleul-Forestier Isabelle , Blanchet Isabelle , Berdal Ariane , Boileau Marie José , Chassaing Nicolas , Clauss François , Delfosse Caroline , De-Saint-Martin Anne , Dahlet Jean-Christophe , Doray Bérénice , Davideau Jean-Luc , Davit-Béal Tiphaine , Dollfus Hélène , Duprez Jean-Pierre , de La Dure Molla Muriel , Dieterich Klauss , Droz Dominique , El Chehadeh Salima , Etienne Olivier , Euvrard Edouard , Faivre Laurence , Fournier Benjamin , Garot Elsa , Grollemund Bruno , Guffon-Fouilhoux Nathalie , Hernandez Magali , Huckert Mathilde , Isidor Bertand , Joseph-Beaudin Clara , Jung Sophie , Lacombe Didier , Lavillaurex Alinoe , Lebrun Marine , Leheup Bruno , Loing Adeline , Lopez Serena , Marlin Sandrine , Morrier Jean-Jacques , Muller-Bolla Michèle , Noirrit Emmanuelle , Odent Sylvie , Paule Gelle Marie , Piard Juliette , Pons Linda , Richard Béatrice , Rossi Massimiliano , Sadones Prune , Schaefer Elise , Sixou Jean-Louis , Soskin Sylvie , Strub Marion , Tardieu Corinne , Thivichon-Prince Béatrice , Toutain Annick , Verloes Alain , Vaysse Frédéric , Wagner Delphine , Amar Juliane Leonhardt , Dostalova Tatjana , El Alloussi Mustapha , Macek Milan , Morkmued Supawich , Noura Zouari , Pungchanchaikul Patimaporn , Qebibo Leeila , Revencu Nicole , Tunisie Sousse , Urzúa Orellana Blanca
TITLE=Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification
JOURNAL=Frontiers in Physiology
VOLUME=14
YEAR=2023
URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1130175
DOI=10.3389/fphys.2023.1130175
ISSN=1664-042X
ABSTRACT=Amelogenesis imperfecta (AI) is a heterogeneous group of genetic rare diseases disrupting enamel development (Smith et al., Front Physiol, 2017a, 8, 333). The clinical enamel phenotypes can be described as hypoplastic, hypomineralized or hypomature and serve as a basis, together with the mode of inheritance, to Witkop’s classification (Witkop, J Oral Pathol, 1988, 17, 547–553). AI can be described in isolation or associated with others symptoms in syndromes. Its occurrence was estimated to range from 1/700 to 1/14,000. More than 70 genes have currently been identified as causative.
Objectives: We analyzed using next-generation sequencing (NGS) a heterogeneous cohort of AI patients in order to determine the molecular etiology of AI and to improve diagnosis and disease management.
Methods: Individuals presenting with so called “isolated” or syndromic AI were enrolled and examined at the Reference Centre for Rare Oral and Dental Diseases (O-Rares) using D4/phenodent protocol (www.phenodent.org). Families gave written informed consents for both phenotyping and molecular analysis and diagnosis using a dedicated NGS panel named GenoDENT. This panel explores currently simultaneously 567 genes. The study is registered under NCT01746121 and NCT02397824 (https://clinicaltrials.gov/).
Results: GenoDENT obtained a 60% diagnostic rate. We reported genetics results for 221 persons divided between 115 AI index cases and their 106 associated relatives from a total of 111 families. From this index cohort, 73% were diagnosed with non-syndromic amelogenesis imperfecta and 27% with syndromic amelogenesis imperfecta. Each individual was classified according to the AI phenotype. Type I hypoplastic AI represented 61 individuals (53%), Type II hypomature AI affected 31 individuals (27%), Type III hypomineralized AI was diagnosed in 18 individuals (16%) and Type IV hypoplastic-hypomature AI with taurodontism concerned 5 individuals (4%). We validated the genetic diagnosis, with class 4 (likely pathogenic) or class 5 (pathogenic) variants, for 81% of the cohort, and identified candidate variants (variant of uncertain significance or VUS) for 19% of index cases. Among the 151 sequenced variants, 47 are newly reported and classified as class 4 or 5. The most frequently discovered genotypes were associated with MMP20 and FAM83H for isolated AI. FAM20A and LTBP3 genes were the most frequent genes identified for syndromic AI. Patients negative to the panel were resolved with exome sequencing elucidating for example the gene involved ie ACP4 or digenic inheritance.
Conclusion: NGS GenoDENT panel is a validated and cost-efficient technique offering new perspectives to understand underlying molecular mechanisms of AI. Discovering variants in genes involved in syndromic AI (CNNM4, WDR72, FAM20A … ) transformed patient overall care. Unravelling the genetic basis of AI sheds light on Witkop’s AI classification.