title: Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections.
abstract: Thoracic aortic aneurysms involving the aortic root and/or ascending aorta can lead to acute aortic dissections. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of the disease, referred to as familial TAAD (FTAAD) that can be inherited in an autosomal dominant manner with variable expression with respect to disease presentation, age of onset and associated features. Whole exome sequencing (WES) has been used to identify causative mutations in novel genes for TAAD. The strategy used to reduce the large number of rare variants identified using WES is to sequence distant relatives with TAAD and filter for heterozygous rare variants that are shared between the relatives, predicted to disrupt protein function and segregate with the TAAD phenotype in other family members. Putative genes are validated by identifying additional families with a causative mutation in the genes. This approach has successfully identified novel genes for FTAAD.
authors: Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston (UT Health), 6431 Fannin, Suite 6.100, Houston, TX 77030, USA. Electronic address: Dianna.M.Milewicz@uth.tmc.edu.
authors: Dianna M
authors: DM
authors: Milewicz
authors: Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston (UT Health), 6431 Fannin, Suite 6.100, Houston, TX 77030, USA.
authors: Ellen S
authors: ES
authors: Regalado
authors: Department of Genome Sciences, University of Washington, Foege Building, 3720 15th Ave NE, Seattle, WA 98195, USA.
authors: Jay
authors: J
authors: Shendure
authors: Department of Genome Sciences, University of Washington, Foege Building, 3720 15th Ave NE, Seattle, WA 98195, USA.
authors: Deborah A
authors: DA
authors: Nickerson
authors: Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston (UT Health), 6431 Fannin, Suite 6.100, Houston, TX 77030, USA.
authors: Dong-chuan
authors: DC
authors: Guo
mesh_terms: D000208:Acute Disease; D000784:Aortic Dissection / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D004252:DNA Mutational Analysis; D059472:Exome; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D014644:Genetic Variation; D015894:Genome, Human; D040941:Heredity; D006801:Humans; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D017422:Sequence Analysis, DNA
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