Dataset Information

A novel variant in fibrillin-1 is responsible for early-onset familial thoracic aortic aneurysms in Marfan patients.

ABSTRACT:

Background

Marfan syndrome (MFS) is an inherited connective tissue disorder that affects the skeletal, ocular, and cardiovascular system. The disease's severity and clinical manifestations vary greatly due to pathogenic variants which, combined with a lack of research on the correlation between MFS's genotype and phenotype, make MFS a challenging disease to diagnose. This study aims to further the understanding of MFS by shedding light on the clinical manifestation of a novel variant in fibrillin-1 (FBN1)-the protein responsible for the genetic defects that lead to MFS.

Methods

A patient was diagnosed with MFS by combining a clinical examination (based on the 2010 revision to Ghent nosology criteria) with a targeted next-generation sequence analysis. The functional analysis of the causal mutation and the clinical details of the affected patient were then analyzed.

Results

The FBN1 heterozygous variant c.5081_5082insT, which is known to delete large fragments from amino acids 1702 to 2871, was found in the proband patient and her son. The two also displayed the skeletal and cardiovascular manifestations of MFS. In addition, the 14-year-old son was identified as having a dilated aortic bulb at the same rupture site of the proband's dissection, and the proband's mother also died at age 32 due to aortic dissection.

Conclusions

The FBN1 variant c.5081_5082insT (p.Leu1694fs*9) is a pathogenic mutation that can cause MFS patients to experience early-onset familial thoracic aortic aneurysms (TAA). We hope that this discovery can provide further insight into the treatment of MFS patients with truncating variants in exons 42-65.

SUBMITTER: Duan Y

PROVIDER: S-EPMC8421937 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

A novel variant in fibrillin-1 is responsible for early-onset familial thoracic aortic aneurysms in Marfan patients.

Duan Yanyu Y Chang Haiying H Ling Jiayuan J Liu Shaoqiang S Zhong Yiming Y

Annals of translational medicine 20210801 15

<h4>Background</h4>Marfan syndrome (MFS) is an inherited connective tissue disorder that affects the skeletal, ocular, and cardiovascular system. The disease's severity and clinical manifestations vary greatly due to pathogenic variants which, combined with a lack of research on the correlation between MFS's genotype and phenotype, make MFS a challenging disease to diagnose. This study aims to further the understanding of MFS by shedding light on the clinical manifestation of a novel variant in ...[more]

PMID: 34532377

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Project description:Thoracic Aortic Aneurysms and Dissections (TAAD) are a major cause of death in the United States. The spectrum of TAAD ranges from genetic disorders, such as Marfan syndrome, to sporadic isolated disease of unknown cause. We hypothesized that genomic copy number variants (CNVs) contribute causally to early onset TAAD (ETAAD). We conducted a genome-wide SNP array analysis of ETAAD patients of European descent who were enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Genotyping was performed on the Illumina Omni-Express platform, using PennCNV, Nexus and CNVPartition for CNV detection. ETAAD patients (n = 108, 100% European American, 28% female, average age 20 years, 55% with bicuspid aortic valves) were compared to 7013 dbGAP controls without a history of vascular disease using downsampled Omni 2.5 data. For comparison, 805 sporadic TAAD patients with late onset aortic disease (STAAD cohort) and 192 affected probands from families with at least two affected relatives (FTAAD cohort) from our institution were screened for additional CNVs at these loci with SNP arrays. We identified 47 recurrent CNV regions in the ETAAD, FTAAD and STAAD groups that were absent or extremely rare in controls. Nine rare CNVs that were either very large (>1 Mb) or shared by ETAAD and STAAD or FTAAD patients were also identified. Four rare CNVs involved genes that cause arterial aneurysms when mutated. The largest and most prevalent of the recurrent CNVs were at Xq28 (two duplications and two deletions) and 17q25.1 (three duplications). The percentage of individuals harboring rare CNVs was significantly greater in the ETAAD cohort (32%) than in the FTAAD (23%) or STAAD (17%) cohorts. We identified multiple loci affected by rare CNVs in one-third of ETAAD patients, confirming the genetic heterogeneity of TAAD. Alterations of candidate genes at these loci may contribute to the pathogenesis of TAAD.

Project description:BackgroundThoracic aortic aneurysms and dissections (TAAD) is a critical condition that often goes undiagnosed with fatal consequences. While majority of the cases are sporadic, more than 20% are inherited as a single gene disorder. The most common familial TAA is Marfan syndrome (MFS), which is primarily caused by mutations in fibrillin-1 (FBN1) gene. Patients with FBN1 mutations are at higher risk for dissection compared to other patients with similar size aneurysms.MethodsFifteen family members were genotyped using Affymetrix-10K genechips. A genome-wide association study was carried out using an autosomal dominant model of inheritance with incomplete penetrance. Mutation screening of all exons and exon-intron boundaries of FBN1 gene which reside near the peak Lod score was carried out by direct sequencing.ResultsThe index case presented with agonizing substernal pain and was found to have TAAD by transthoracic echocardiogram. The family history was significant for 3 first degree relatives with TAA. Nine additional family members were diagnosed with TAA by echocardiography examinations. The affected individuals had no syndromic features. A genome-wide analysis of linkage mapped the disease gene to a single locus on chromosome 15q21 with a peak Lod score of 3.6 at fibrillin-1 (FBN1) gene locus (odds ratio > 4000:1 in favour of linkage), strongly suggesting that FBN1 is the causative gene. No mutation was identified within the exons and exon-intron boundaries of FBN1 gene that segregated with the disease. Haplotype analysis identified additional mutation carriers who had previously unknown status due to borderline dilation of the ascending aorta.ConclusionsA familial non-syndromic TAAD is strongly associated with the FBN1 gene locus and has a malignant disease course often seen in MFS patients. This finding indicates the importance of obtaining detailed family history and echocardiographic screening of extended relatives of patients with non-syndromic TAAD to improve the outcome. In addition, association of non-syndromic TAAD with the Marfan disease gene locus poses the question whether secondary prevention strategies employed for Marfan syndrome patients should be applied to all patients with familial TAAD.

Dataset Information

A novel variant in fibrillin-1 is responsible for early-onset familial thoracic aortic aneurysms in Marfan patients.

Background

Methods

Results

Conclusions

Publications

A novel variant in fibrillin-1 is responsible for early-onset familial thoracic aortic aneurysms in Marfan patients.

Similar Datasets

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