A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement.

BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. 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.journal articleresearch support, non-u.s. gov't2016 Feb2015 10 26importe

Protocole de soins pour le traitement des agénésies dentaires multiples liéés à une maladie rare chez l'enfant (Bilan des expertises réalisées dans le cadre des demandes d'affection longue durée hors liste)

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Diagnostic et traitements du bruxisme chez l'enfant

REIMS-BU Santé (514542104) / SudocSTRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocLILLE2-UFR Odontologie (593502202) / SudocSudocFranceF

La sédation intraveineuse au propofol pour les soins dentaires chez les personnes en situation de handicap (étude rétrospective dans le cadre du réseau Handident Alsace)

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Oral anticoagulant periprocedural management in patients undergoing an oral, dental implant or periodontal surgery: a prospective national observational survey

Background: Oral surgery is a frequent invasive procedure in patients on oral anticoagulants. In usual care, the periprocedural management of these patients is questioned, with conflicting guidelines for patients on direct oral anticoagulants (DOACs). Objectives: To assess the risk of hemorrhagic and thromboembolic events during the periprocedural period (5 days before and 30 days after the oral invasive procedure). Methods: The PRatiques Anticoagulants oraux DIrects Chirurgie Orale Study (NCT 03150303) is a prospective noninterventional national study including patients receiving long-term oral anticoagulants (duration of treatment of at least 1 month) and referred to dental surgeons for an invasive procedure. Hemorrhagic and thromboembolic events and death on days 2, 7, and 30 were reported and analyzed according to anticoagulant management (interruption/continuation). Bleedings were classified according to the International Society on Thrombosis and Haemostasis classification after blinded review. Results: Overall, between July 2017 and December 2019, 523 patients (mean age 74) were recruited (345 on DOACs and 178 on vitamin K antagonists [VKAs]). During the periprocedural period, 62 events (11.8 events per 100 person-month [PM]) occurred, all local bleedings, in 50 patients (90.3% during the 7 days). The incidence of postoperative bleeding was greater in patients who continued on DOACs compared with patients who continued on VKAs (15.9/100 PM vs 5.9/100 PM; P = .003). Conversely, no significant difference was observed between patients with DOAC discontinuation and patients with VKA continuation (6.2/100 PM vs 5.9/100 PM; P = .75). Conclusion: In patients on anticoagulants undergoing an invasive oral procedure, the risk of bleeding occurs mainly within the 7 days following the procedure. Our data suggest the benefit of short perioperative discontinuation of DOACs

A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement

International audienceBackground Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. 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 NCT0239782

Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop’s classification

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