Characterization of large genomic deletions in the FBN1 gene using multiplex ligation-dependent probe amplification

<p>Abstract</p> <p>Background</p> <p>Connective tissue diseases characterized by aortic aneurysm, such as Marfan syndrome, Loeys-Dietz syndrome and Ehlers Danlos syndrome type IV are heterogeneous and despite overlapping phenotypes, the natural history, clinical manifestations and interventional course for each diagnosis can be quite unique. The majority of mutations involved in the etiology of these disorders are missense and nonsense mutations. However, large deletions and duplications undetected by sequencing may be implicated in their pathogenesis, and may explain the apparent lack of genotype-phenotype correlation in a subset of patients. The objective of this study was to search for large pathogenic deletions and/or duplications in the <it>FBN1, TGFβR1</it>, and <it>TGFβR2 </it>genes using multiplex-ligation dependent probe amplification (MLPA) in patients with aortopathy, in whom no mutations in the <it>FBN1, TGFβR1</it>, and <it>TGFβR2 </it>genes were identified by sequencing.</p> <p>Methods</p> <p>The study included 14 patients from 11 unrelated families with aortic aneurysm. Of those, six patients (including 3 first-degree relatives), fulfilled the revised Ghent criteria for Marfan syndrome, and eight had predominantly aortic aneurysm/dilatation with variable skeletal and craniofacial involvement. MLPA for <it>FBN1, TGFβR1</it>, and <it>TGFβR2 </it>was carried out in all patients. A 385 K chromosome 15 specific array was used in two patients with a deletion of the entire <it>FBN1 </it>in order to define its size and boundaries.</p> <p>Results</p> <p>We identified two novel large deletions in the <it>FBN1 </it>gene in four patients of two unrelated families who met clinical diagnostic criteria for Marfan syndrome. One patient was found to have a <it>FBN1 </it>deletion encompassing exons 1-5. The other three patients had a 542 Kb deletion spanning the whole <it>FBN1 </it>gene and five additional genes (<it>SLC24A5, MYEF2, CTXN2, SLC12A1, DUT</it>) in the chromosome 15.</p> <p>Conclusions</p> <p>Our findings expand the number of large <it>FBN1 </it>deletions, and emphasize the importance of screening for large genomic deletions in connective tissue disorders featuring aortopathies, especially for those with classic Marfan phenotype.</p

RECURRENT GENOMIC COPY NUMBER VARIANTS IMPLICATE NEW CANDIDATE GENES FOR EARLY ONSET BICUSPID AORTIC VALVE DISEASE

Background Bicuspid Aortic Valve (BAV), the most common adult congenital heart defect, is a major cause of aortic insufficiency or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications to sporadic late onset disease. We hypothesize that genomic copy number variants (CNVs) modify the penetrance and severity of early onset BAV (EBAV). Methods We performed genome-wide microarray analysis of 140 EBAV probands who were enrolled in the UTHealth Bicuspid Aortic Valve Research Registry. CNVs were detected in Illumina Global Screening Array genotypes using PennCNV, Nexus and CNVPartition algorithms. The EBAV cohort (22% female, mean age 18) was compared to 15,414 controls without known cardiac disease from the Database of Genotypes and Phenotypes. Only CNV calls that contained at least six consecutive variants, were identified by at least two algorithms and intersect with known genes were included. For comparison, 140 older late presenting BAV patients (LBAV group) and 58 BAV probands with early onset thoracic aortic disease (ETAD group) were assayed using identical methods. CNV burden and associations were tested using PLINK (v1.07). CNVs were validated using quantitative PCR. Results We identified 7 recurrent CNV regions that are absent or extremely rare (frequency &lt;0.1%) in controls and 1 polymorphic duplication that is enriched in EBAV cases. Six of these regions are shared by EBAV and LBAV or ETAD cases and involve candidate genes that interact with each other during heart development. Four CNVs involve genes that cause BAV when mutated. The largest and most prevalent of the recurrent CNVs are at 2q37.3 (1 duplication, 8 deletions), 22q11.21 (3 duplications, 2 deletions) and Xp22.33 (8 duplications). The rate of large (&gt;200 Kb) genic deletions and the percentage of individuals with rare genic CNVs (27%) are both increased in the EBAV cohort in comparison to the LBAV (9%) or control (10%) cohorts (empiric P &lt; 1×10-5). Conclusion We identified rare CNVs in one quarter of EBAV patients, implicating alterations of candidate genes in these loci in the pathogenesis of BAV

Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy

Item does not contain fulltextBACKGROUND: The Pediatric Heart Network designed a clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in children and young adults with Marfan syndrome randomized to receive atenolol or losartan. We report here the characteristics of the screened population and enrolled subjects. METHODS AND RESULTS: Between 2007 and 2011, 21 clinical sites randomized 608 subjects, aged 6 months to 25 years who met the original Ghent criteria and had a body surface area-adjusted aortic root diameter z-score >3.0. The mean age at study entry was 11.2 years, 60% were male, and 25% were older teenagers and young adults. The median aortic root diameter z-score was 4.0. Aortic root diameter z-score did not vary with age. Mitral valve prolapse and mitral regurgitation were more common in females. Among those with a positive family history, 56% had a family member with aortic surgery, and 32% had a family member with a history of aortic dissection. CONCLUSIONS: Baseline demographic, clinical, and anthropometric characteristics of the randomized cohort are representative of patients in this population with moderate to severe aortic root dilation. The high percentage of young subjects with relatives who have had aortic dissection or surgery illustrates the need for more definitive therapy; we expect that the results of the study and the wealth of systematic data collected will make an important contribution to the management of individuals with Marfan syndrome