Whole exome sequencing in an Italian family with isolated maxillary canine agenesis and canine eruption anomalies.

Ersilia Barbato, Alice Traversa, Rosanna Guarnieri, Agnese Giovannetti, Maria Luce Genovesi, Maria Rosa Magliozzi, Stefano Paolacci, Andrea Ciolfi, Simone Pizzi, Roberto Di Giorgio, Marco Tartaglia, Antonio Pizzuti, Viviana Caputo

Journal: Archives of oral biology 2018;91():96-102

PMID: 29705498

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Abstract

OBJECTIVE

The aim of this study was the clinical and molecular characterization of a family segregating a trait consisting of a phenotype specifically involving the maxillary canines, including agenesis, impaction and ectopic eruption, characterized by incomplete penetrance and variable expressivity.

DESIGN

Clinical standardized assessment of 14 family members and a whole-exome sequencing (WES) of three affected subjects were performed. WES data analyses (sequence alignment, variant calling, annotation and prioritization) were carried out using an in-house implemented pipeline. Variant filtering retained coding and splice-site high quality private and rare variants. Variant prioritization was performed taking into account both the disruptive impact and the biological relevance of individual variants and genes. Sanger sequencing was performed to validate the variants of interest and to carry out segregation analysis.

RESULTS

Prioritization of variants "by function" allowed the identification of multiple variants contributing to the trait, including two concomitant heterozygous variants in EDARADD (c.308C>T, p.Ser103Phe) and COL5A1 (c.1588G>A, p.Gly530Ser), specifically associated with a more severe phenotype (i.e. canine agenesis). Differently, heterozygous variants in genes encoding proteins with a role in the WNT pathway were shared by subjects showing a phenotype of impacted/ectopic erupted canines.

CONCLUSIONS

This study characterized the genetic contribution underlying a complex trait consisting of isolated canine anomalies in a medium-sized family, highlighting the role of WNT and EDA cell signaling pathways in tooth development.

Address: Department of Oral and Maxillo Facial Sciences, Sapienza University of Rome, Via Caserta 6, 00161, Rome, Italy. Electronic address: [email protected].; Clinical Genomics Unit, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini 1, 71013, San Giovanni Rotondo, FG, Italy. Electronic address: [email protected].; Department of Oral and Maxillo Facial Sciences, Sapienza University of Rome, Via Caserta 6, 00161, Rome, Italy. Electronic address: [email protected].; Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy. Electronic address: [email protected].; Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy. Electronic address: [email protected].; Department of Oral and Maxillo Facial Sciences, Sapienza University of Rome, Via Caserta 6, 00161, Rome, Italy. Electronic address: [email protected].; Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy. Electronic address: [email protected].; Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Viale di San Paolo 15, 00146, Rome, Italy. Electronic address: [email protected].; Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Viale di San Paolo 15, 00146, Rome, Italy. Electronic address: [email protected].; Department of Oral and Maxillo Facial Sciences, Sapienza University of Rome, Via Caserta 6, 00161, Rome, Italy. Electronic address: [email protected].; Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Viale di San Paolo 15, 00146, Rome, Italy. Electronic address: [email protected].; Clinical Genomics Unit, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini 1, 71013, San Giovanni Rotondo, FG, Italy; Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy. Electronic address: [email protected].; Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy. Electronic address: [email protected].

DOI: 10.1016/j.archoralbio.2018.04.011

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MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Anodontia, Calcium-Binding Proteins, Collagen Type V, Cuspid, DNA Mutational Analysis, Ectodysplasins, Edar-Associated Death Domain Protein, Female, Fetal Proteins, Gene Frequency, Heterozygote, Humans, Italy, Male, Maxilla, Middle Aged, Mutation, Nerve Tissue Proteins, Pedigree, Phenotype, Radiography, Panoramic, Sequence Alignment, T-Box Domain Proteins, Thrombospondins, Tooth Eruption, Exome Sequencing, Wnt Signaling Pathway, Young Adult, Brachyury Protein