02369nas a2200265   4500008004100000022001400041245009900055210006900154260001300223300001100236490000600247520144900253100003301702700002801735700002701763700002201790700002301812700001901835700002401854700003201878700002001910700001901930700002501949856012901974       2014                        eng d  a2324-926900aDeciphering intrafamilial phenotypic variability by exome sequencing in a Bardet-Biedl family.0 aDeciphering intrafamilial phenotypic variability by exome sequen  c2014 Mar  a124-330 v23 a<p>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. </p>1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aSantoyo-López, Javier1 aVela-Boza, Alicia1 aBravo-Gil, Nereida1 aRueda, Antonio1 aGarcía-Alonso, Luz1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo  uhttps://www.clinbioinfosspa.es/content/deciphering-intrafamilial-phenotypic-variability-exome-sequencing-bardet-biedl-family