Deciphering intrafamilial phenotypic variability by exome sequencing in a Bardet–Biedl family

María González-del Pozo, Cristina Méndez-Vidal, Javier Santoyo-Lopez, Alicia Vela-Boza, Nereida Bravo-Gil, Antonio Rueda, Luz García-Alonso, Carmen Vázquez-Marouschek, Joaquín Dopazo, Salud Borrego, Guillermo Antiñolo

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)124-133
Number of pages10
JournalMolecular Genetics and Genomic Medicine
Issue number2
Publication statusPublished - 3 Dec 2013

Keywords / Materials (for Non-textual outputs)

  • bardet–biedl syndrome
  • intrafamilial variability
  • MKKS
  • NGS
  • NPHP4


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