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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 ; Instituto de Salud Carlos III (ISCIII) ; Spanish Ministry of Economy and Competitiveness (PI1102923) ; Regional Ministry of Economy, Innovation, Science and Employment of the Autonomous Government of Andalusia (CTS-03687) ; Regional Ministry of Health of the Autonomous Government of Andalusia (PI100154), (PCT-30000-2009-12) ; INNPLANTA (PCT-300000-2010-007) ; Ciber de Enfermedades raras (CIBERER) ; Foundation Ramon Areces (CIVP16A1856) ; Spanish Ministry of Science and Innovation (BIO2011-27069) ; Conselleria de Educacio of the Valencia Community (PROMETEO/2010/001)

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/. ; Spanish Ministry of Economy and Competitiveness [SAF2017-88908-R, PT17/0009/0006 to J.D.; PI19/00321 and CIBERER ACCI-06/07/0036 to C.A., PI14-948, PI171659 and CIBERER ACCI-06/07/0036 to M.A.M.P.]; Regional Government of Madrid, RAREGenomicsCM [B2017/BMD-3721 to C.A. and B2017/BMD3721 to M.A.M.P.]; all co-funded with European Regional Development Funds (ERDF) as well as EU H2020INFRADEV-1-2015-1 ELIXIR-EXCELERATE [676559]; University Chair UAM-IIS-FJD of Genomic Medicine and the Ramon Areces Foundation also supported this work. Funding for open access charge: Spanish Ministry of Economy and Competitiveness [SAF2017-88908-R]. ; Sí

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/. ; Spanish Ministry of Economy and Competitiveness [SAF2017-88908-R, PT17/0009/0006 to J.D.; PI19/00321 and CIBERER ACCI-06/07/0036 to C.A., PI14-948, PI17-1659 and CIBERER ACCI-06/07/0036 to M.A.M.P.]; Regional Government of Madrid, RAREGenomics-CM [B2017/BMD-3721 to C.A. and B2017/BMD3721 to M.A.M.P.]; all co-funded with European Regional Development Funds (ERDF) as well as EU H2020-INFRADEV-1-2015-1 ELIXIR-EXCELERATE [676559]; University Chair UAM-IIS-FJD of Genomic Medicine and the Ramon Areces Foundation also supported this work. Funding for open access charge: Spanish Ministry of Economy and Competitiveness [SAF2017-88908-R]. ; Peer reviewed