title: Deciphering intrafamilial phenotypic variability by exome sequencing in a Bardet-Biedl family.
abstract: Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing-based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick-Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocio/Consejo Superior de Investigaciones Científicas/University of Seville Seville, Spain ; Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville, Spain.
authors.forename: María
authors.initials: M
authors.lastname: González-Del Pozo
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocio/Consejo Superior de Investigaciones Científicas/University of Seville Seville, Spain ; Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Méndez-Vidal
authors.affiliation: Medical Genome Project, Genomics and Bioinformatics Platform of Andalusia (GBPA) Seville, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Santoyo-Lopez
authors.affiliation: Medical Genome Project, Genomics and Bioinformatics Platform of Andalusia (GBPA) Seville, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Vela-Boza
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocio/Consejo Superior de Investigaciones Científicas/University of Seville Seville, Spain.
authors.forename: Nereida
authors.initials: N
authors.lastname: Bravo-Gil
authors.affiliation: Medical Genome Project, Genomics and Bioinformatics Platform of Andalusia (GBPA) Seville, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rueda
authors.affiliation: Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF) Valencia, Spain.
authors.forename: Luz
authors.initials: L
authors.lastname: García-Alonso
authors.affiliation: Department of Ophthalmology, University Hospital Virgen del Rocío Seville, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Vázquez-Marouschek
authors.affiliation: Medical Genome Project, Genomics and Bioinformatics Platform of Andalusia (GBPA) Seville, Spain ; Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF) Valencia, Spain ; Functional Genomics Node (INB), CIPF Valencia, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocio/Consejo Superior de Investigaciones Científicas/University of Seville Seville, Spain ; Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville, Spain.
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocio/Consejo Superior de Investigaciones Científicas/University of Seville Seville, Spain ; Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville, Spain ; Medical Genome Project, Genomics and Bioinformatics Platform of Andalusia (GBPA) Seville, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
keywords: Bardet–Biedl Syndrome; MKKS; NGS; NPHP4; intrafamilial variability