title: Whole exome sequencing implicates an INO80D mutation in a syndrome of aortic hypoplasia, premature atherosclerosis, and arterial stiffness.
abstract: 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 2 siblings with aortic hypoplasia, calcific atherosclerosis, systolic hypertension, and premature cataract.
  
  
  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 a different exome analyses pipeline. The 2 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 multiprotein 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 affect 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.
authors.affiliation: From the Division of Cardiovascular Diseases (K.S., A.K.D., I.J.K.) and Biomedical Statistics and Informatics, Departments of Health Sciences Research and Laboratory Medicine and Pathology (E.W.K.), Mayo Clinic, Rochester MN.
authors.forename: Khader
authors.initials: K
authors.lastname: Shameer
authors.affiliation: From the Division of Cardiovascular Diseases (K.S., A.K.D., I.J.K.) and Biomedical Statistics and Informatics, Departments of Health Sciences Research and Laboratory Medicine and Pathology (E.W.K.), Mayo Clinic, Rochester MN.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Klee
authors.affiliation: From the Division of Cardiovascular Diseases (K.S., A.K.D., I.J.K.) and Biomedical Statistics and Informatics, Departments of Health Sciences Research and Laboratory Medicine and Pathology (E.W.K.), Mayo Clinic, Rochester MN.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Dalenberg
authors.affiliation: From the Division of Cardiovascular Diseases (K.S., A.K.D., I.J.K.) and Biomedical Statistics and Informatics, Departments of Health Sciences Research and Laboratory Medicine and Pathology (E.W.K.), Mayo Clinic, Rochester MN. kullo.iftikhar@mayo.edu.
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000328:Adult; D000368:Aged; D000375:Aging; D001018:Aortic Diseases / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics*; D002386:Cataract / Q000235:genetics*; D002843:Chromatin; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins; D059472:Exome; D005192:Family Health; D005260:Female; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D059289:Vascular Stiffness / Q000235:genetics*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C524421:INO80 protein, human
keywords: INO80D protein, human; aortic hypoplasia; arterial stiffness; atherosclerosis; chromatin assembly and disassembly; genetics