Abstract
Inherited aortopathy, which is characterized by a high risk of fatal aortic aneurysms/dissections, can occur secondarily to several syndromes. To identify genetic mutations and help make a precise diagnosis, we designed a gene panel containing 15 genes responsible for inherited aortopathy and tested 248 probands with aortic disease or Marfan syndrome. The results showed that 92 individuals (37.1%) tested positive for a (likely) pathogenic mutation, most of which were FBN1 mutations. We found that patients with a FBN1 truncating or splicing mutation were more prone to developing severe aortic disease or valvular disease. To date, this is the largest reported cohort of Chinese patients with aortic disease who have undergone genetic testing. Therefore, it can serve as a considerable dataset of next generation sequencing data analysis of Chinese population with inherited aortopathy. Additionally, according to the accumulated data, we optimized the analysis pipeline by adding quality control steps and lowering the false positive rate.
Highlights
Inherited aortopathy, which is characterized by aortic dilation or aortic aneurysms/dissection, may be syndromic, as occurs in Marfan syndrome (MFS)[1], Loeys-Dietz syndrome (LDS)[2], Ehlers-Danlos syndrome, vascular type[3], and Shprintzen-Goldberg syndrome (SGS)[4], or non-syndromic, in which abnormalities are restricted to the aorta[5]
Sequencing of the 15 aortopathy genes (Table 1) in the 248 samples yielded a mean depth of ~350X and coverage of 98.7%
Based on our growing data and experience, we developed an automated and optimal analysis plugin named iAorta, which allowed us to automatically pick up suspected pathogenic mutations or variant of unknown significance (VUS) from polymorphism or false-positive variants, add quality control steps to assess the sequencing quality and indicate possible false-negative variants, and remove frequent false-positive mutations based on our 248 samples
Summary
Inherited aortopathy, which is characterized by aortic dilation or aortic aneurysms/dissection, may be syndromic, as occurs in Marfan syndrome (MFS)[1], Loeys-Dietz syndrome (LDS)[2], Ehlers-Danlos syndrome, vascular type (vEDS)[3], and Shprintzen-Goldberg syndrome (SGS)[4], or non-syndromic, in which abnormalities are restricted to the aorta[5]. These diseases have their own unique characteristics, they share some clinical manifestations, which makes the precise diagnosis and treatment strategy difficult. We optimized the analysis pipeline by adding quality control steps and lowering the false positive rate
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