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

ABSTRACT: 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.

SUBMITTER: Prasad MK

PROVIDER: S-EPMC4752661 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Prasad Megana K MK Geoffroy Véronique V Vicaire Serge S Jost Bernard B Dumas Michael M Le Gras Stéphanie S Switala Marzena M Gasse Barbara B Laugel-Haushalter Virginie V Paschaki Marie M Leheup Bruno B Droz Dominique D Dalstein Amelie A Loing Adeline A Grollemund Bruno B Muller-Bolla Michèle M Lopez-Cazaux Séréna S Minoux Maryline M Jung Sophie S Obry Frédéric F Vogt Vincent V Davideau Jean-Luc JL Davit-Beal Tiphaine T Kaiser Anne-Sophie AS Moog Ute U Richard Béatrice B Morrier Jean-Jacques JJ Duprez Jean-Pierre JP Odent Sylvie S Bailleul-Forestier Isabelle I Rousset Monique Marie MM Merametdijan Laure L Toutain Annick A Joseph Clara C Giuliano Fabienne F Dahlet Jean-Christophe JC Courval Aymeric A El Alloussi Mustapha M Laouina Samir S Soskin Sylvie S Guffon Nathalie N Dieux Anne A Doray Bérénice B Feierabend Stephanie S Ginglinger Emmanuelle E Fournier Benjamin B de la Dure Molla Muriel M Alembik Yves Y Tardieu Corinne C Clauss François F Berdal Ariane A Stoetzel Corinne C Manière Marie Cécile MC Dollfus Hélène H Bloch-Zupan Agnès A

Journal of medical genetics 20151026 2

<h4>Background</h4>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.<h4>Methods</h4>We designed an NGS gene panel tha ...[more]

PMID: 26502894

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Project description:BackgroundDefects in the development of the first and second pharyngeal arches and their derivatives result in abnormal formation of the craniofacial complex, consequently giving rise to facial dysostoses (FDs). FDs represent a group of rare and highly heterogeneous disease entities that encompass mandibulofacial dysostoses (MFDs) with normal extremities and acrofacial dysostoses (AFDs) with limb anomalies in addition to craniofacial defects.MethodsWe examined 11 families with variable clinical symptoms of FDs, in most of which only one member was affected. We applied two custom gene panels-first comprising 37 genes related to the genetic disorders of craniofacial development such as FDs (On-Demand AmpliSeq Thermo Fisher Scientific gene panel with two primer pools) and second composed of 61 genes and 11 single nucleotide variants (SNVs) known to be involved in the development of skull malformations, mainly in the form of craniosynostoses (SureSelect Agilent Technologies). Targeted next-generation sequencing (NGS) was performed using the Ion Torrent S5 platform. To confirm the presence of each detected variant, we have analyzed a genomic region of interest using Sanger sequencing.ResultsIn this paper, we summarized the results of custom targeted gene panel sequencing in the cohort of sixteen patients from 11 consecutive families affected by distinct forms of FDs. We have found three novel pathogenic variants in the TCOF1 gene-c.2145_2148dupAAAG p.(Ser717Lysfs ∗42), c.4370delA p.(Lys1457Argfs ∗118), c.83G>C p.(Arg28Pro) causing Treacher Collins syndrome type 1, two novel missense variants in the EFTUD2 gene-c.491A>G p.(Asp164Gly) and c.779T>A p.(Ile260Asn) in two female patients affected by acrofacial dysostosis Guion-Almeida type, one previously reported-c.403C>T (p.Arg135Cys), as well as one novel missense variant-c.128C>T p.(Pro43Leu) in the DHODH gene in the male patient with Miller syndrome and finally one known pathogenic variant c.574G>T p.(Glu192∗) in the SF3B4 gene in the patient with Nager syndrome.ConclusionOur study confirms the efficiency and clinical utility of the targeted gene panel sequencing and shows that this strategy is suitable and efficient in the molecular screening of variable forms of FDs.

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

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

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