RESUMEN
BACKGROUND: The 20% of thoracic aortic aneurysms and dissections independent from the main connective tissue syndromes and expected to be familial has gained importance over the past years. The more frequent pattern of inheritance of these nonsyndromic cases is autosomal dominant with incomplete penetrance and variable expression. Although many candidate genes exist, unresolved familial cases suggest still unravelled genetic variation. The main purpose of this study was to establish the genetic diagnosis of one of those. MATERIALS AND METHODS: To begin with, we applied a candidate gene approach based on both traditional and a customized massive parallel sequencing panel, followed by Illumina HiSeq 2000 whole exome sequencing of four family members affected by early-onset thoracic aortic disease and two unaffected relatives. We prioritized whole exome sequencing results based on variant location, type and frequency in general population databases and performed segregation analysis in 14 family members using traditional sequencing. RESULTS: After the negative results we obtained with candidate gene approaches, the analysis and prioritization of whole exome sequencing results brought out the heterozygote c.530G>A:p.Arg177Gln PRKG1 variant (NM_001098512), located in one of the aortic smooth muscle cell contractile apparatus genes. This candidate variant segregated with thoracic aortic disease, as it was present in seven affected and absent in five unaffected family members, further supporting its causality. CONCLUSIONS: This was the second time PRKG1 was associated with thoracic aortic disease, highlighting and reaffirming it as a strong candidate for gene-based diagnosis of nonsyndromic early-onset cases.