IADR Abstract Archives
NGS Revisits the Genetic Basis of Amelogenesis Imperfecta
Objectives: Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterised by enamel defects. To date, mutations in >20 genes have been implicated in either isolated or syndromic AI. The aim of this project is to identify the gene and detail the genotype behind each phenotype of AI
Methods: We used a next-generation sequencing (NGS) panel targeting 585 known or candidate genes in dental disorders to screen a cohort of 61 patients enrolled within the CRMR, reference centre for orodental manifestations of rare diseases, within the Höpitaux Universitires de Strasbourg with isolated and syndromic forms of AI.
Results: We were able to identify the molecular defect underlying the patients’ phenotypes in 15 cases (~25%), suggesting that several additional genes mutated in AI remain to be discovered. Interestingly, mutations in COL17A1 were the most frequent cause of isolated AI in our cohort, accounting for 8% of patients with isolated AI. Furthermore, NGS-based screening of multiple AI genes allowed us to identify a rare case of digenic inheritance in AI, with unlinked heterozygous mutations in COL17A1 and LAMA3 modifying the severity of the phenotype. Finally, sequencing in a seven-year-old patient presenting with isolated AI revealed the presence of a homozygous missense mutation in CNNM4, mutations in which result in Jalili syndrome, a diagnosis that was subsequently confirmed by ophthalmological investigation.
Conclusions: Therefore, we demonstrate that a large proportion of the genetic heterogeneity of AI remains unsolved and that non-Mendelian inheritance patterns exist in AI. We also demonstrate that the dental clinic may be a gateway for the diagnosis and management of rare genetic disorders. This EU-funded project (ERDF) A27 "Oro-dental manifestations of rare diseases" is supported by the RMT-TMO Offensive Sciences initiative, INTERREG IV and INTERREG V RARENET program. www.genosmile.eu.
Methods: We used a next-generation sequencing (NGS) panel targeting 585 known or candidate genes in dental disorders to screen a cohort of 61 patients enrolled within the CRMR, reference centre for orodental manifestations of rare diseases, within the Höpitaux Universitires de Strasbourg with isolated and syndromic forms of AI.
Results: We were able to identify the molecular defect underlying the patients’ phenotypes in 15 cases (~25%), suggesting that several additional genes mutated in AI remain to be discovered. Interestingly, mutations in COL17A1 were the most frequent cause of isolated AI in our cohort, accounting for 8% of patients with isolated AI. Furthermore, NGS-based screening of multiple AI genes allowed us to identify a rare case of digenic inheritance in AI, with unlinked heterozygous mutations in COL17A1 and LAMA3 modifying the severity of the phenotype. Finally, sequencing in a seven-year-old patient presenting with isolated AI revealed the presence of a homozygous missense mutation in CNNM4, mutations in which result in Jalili syndrome, a diagnosis that was subsequently confirmed by ophthalmological investigation.
Conclusions: Therefore, we demonstrate that a large proportion of the genetic heterogeneity of AI remains unsolved and that non-Mendelian inheritance patterns exist in AI. We also demonstrate that the dental clinic may be a gateway for the diagnosis and management of rare genetic disorders. This EU-funded project (ERDF) A27 "Oro-dental manifestations of rare diseases" is supported by the RMT-TMO Offensive Sciences initiative, INTERREG IV and INTERREG V RARENET program. www.genosmile.eu.