BackgroundOrodental 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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 numbersNCT01746121 and NCT02397824.

Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis.

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IntroductionAmelogenesis imperfecta is an inherited disease characterized by generalized structural abnormalities of the enamel on all teeth, including both primary and permanent dentition. To the best of our knowledge, this is the first case report of a rare association of amelogenesis imperfecta, platyspondyly, and bicytopenia.Case presentationA 5-year-old Moroccan boy was examined in the Centre for Dental Consultation and Treatment, Faculty of Dentistry, Rabat. He was a child of consanguineous parents (first degree). The child failed to thrive (−4 standard deviation score) and displayed delayed overall development. A dental examination revealed a hypoplastic amelogenesis imperfecta with a bacterial biofilm deposit on tooth surfaces. A complete blood count revealed bicytopenia (normocytic-normochromic anemia with thrombocytopenia). A radiographic examination of the spinal column showed a deviation of the spine in the frontal plane in the form of thoracolumbar scoliosis. The interpedicular distance was not expanded; but a mild platyspondyly exists, especially pronounced in T11 and T12.ConclusionsNo other family members presented amelogenesis imperfecta, bicytopenia, or platyspondyly. The consanguineous marriage suggested an autosomal recessive mode of inheritance. Further studies are necessary to clarify the genetic defect producing this syndrome, and the symptomatic associations of amelogenesis imperfecta, platyspondyly and bicytopenia.