Whole Exome Sequencing Implicates an INO80D Mutation in a Syndrome of Aortic Hypoplasia, Premature Atherosclerosis, and Arterial Stiffness
Background—Massively parallel, high-throughput sequencing technology is helping to generate new insights into the genetic basis of human diseases. We used whole exome sequencing to identify the mutation underlying a syndrome affecting two siblings with aortic hypoplasia, calcific atherosclerosis, systolic hypertension, and premature cataract.
Materials and Results—Exonic regions were captured and sequenced using a next-generation sequencing platform to generate 100 bases paired-end reads. A computational genomic data analysis pipeline was used to perform quality control, align reads to a reference genome and identify genetic variants. Findings were confirmed using an independent exome analyses pipeline. The two siblings were homozygous for a rare missense mutation (Ser818Cys) in INO80D, a subunit of the human INO80 chromatin remodeling complex. Homozygosity mapping and Sanger sequencing confirmed that the mutation is located in one of the runs of homozygosity on chromosome 2. INO80D encodes a key subunit of the human IN080 complex, a multi-protein complex involved in DNA binding, chromatin modification, organization of chromosome structure, and ATP-dependent nucleosome sliding. By introducing a new disulphide bond in the protein product and also disrupting the composition of low-complexity regions, the Ser818Cys mutation may impact INO80D function, protein-protein interactions and chromatin remodeling.
Conclusions—Our findings suggest a link between the Ser818Cys mutation in INO80D, a subunit of the human INO80 chromatin remodeling complex, and accelerated arterial aging.
- arterial aging
- rare variants
- chromatin remodeling
- INO80 complex
- gene mutation
- Received May 23, 2013.
- Revision received June 6, 2014.
- Accepted June 27, 2014.