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.
Acta Ophthalmol. 2011: 89: e12–e22
.
Purpose: To investigate new genetic risk factors and replicate reported associations with advanced age‐related macular degeneration (AMD) in a prospective ...case–control study developed with a Spanish cohort.
Methods: Three hundred and fifty‐three unrelated patients with advanced AMD (225 with atrophic AMD, 57 with neovascular AMD, and 71 with mixed AMD) and 282 age‐matched controls were included. Functional and tagging SNPs in 55 candidate genes were genotyped using the SNPlexTM genotyping system. Single SNP and haplotype association analysis were performed to determine possible genetic associations; interaction effects between SNPs were also investigated.
Results: In agreement with previous reports, ARMS2 and CFH genes were strongly associated with AMD in the studied Spanish population. Moreover, both loci influenced risk independently giving support to different pathways implicated in AMD pathogenesis. No evidence for association of advanced AMD with other previous reported susceptibility genes, such as CST3, CX3CR1, FBLN5, HMCN1, PON1, SOD2, TLR4, VEGF and VLDLR, was detected. However, two additional genes appear to be candidate markers for the development of advanced AMD. A variant located at the 3′ UTR of the FGF2 gene (rs6820411) was highly associated with atrophic AMD, and the functional SNP rs3112831 at ABCA4 showed a marginal association with the disease.
Conclusion: We performed a large gene association study in advanced AMD in a Spanish population. Our findings show that CFH and ARMS2 genes seem to be the principal risk loci contributing independently to AMD in our cohort. We report new significant associations that could also influence the development of advanced AMD. These findings should be confirmed in further studies with larger cohorts.
The implication of copy number variations in familial heart disease is known, although in-depth knowledge is lacking; hence, more studies are needed to further our understanding. Massively parallel ...sequencing, thanks to its recent surge in use, is emerging as a valid tool for the detection of this type of variant, through the use of appropriate software.
We conducted a study with 182 patients diagnosed with mendelian cardiovascular diseases who underwent sequencing using a cardiac gene panel and then a specific calling process for copy number variations (CNVs) with ExomeDepth software, which provides us with a Bayes factor (BF), a score of the probability that a CNV detected is true.
After a rigorous CNV prioritization process, we confirmed the variants obtained by MLPA or SNP-based array, finding three real CNVs in five individuals in the MYH11, FBN1 and PDMI7 genes.
The confirmed CNVs present in all cases BF values > 60, thus establishing a threshold to consider real CNVs in the calling process carried out by ExomeDepth on our gene panel.
Most studies of European genetic diversity have focused on large-scale variation and interpretations based on events in prehistory, but migrations and invasions in historical times could also have ...had profound effects on the genetic landscape. The Iberian Peninsula provides a suitable region for examination of the demographic impact of such recent events, because its complex recent history has involved the long-term residence of two very different populations with distinct geographical origins and their own particular cultural and religious characteristics—North African Muslims and Sephardic Jews. To address this issue, we analyzed Y chromosome haplotypes, which provide the necessary phylogeographic resolution, in 1140 males from the Iberian Peninsula and Balearic Islands. Admixture analysis based on binary and Y-STR haplotypes indicates a high mean proportion of ancestry from North African (10.6%) and Sephardic Jewish (19.8%) sources. Despite alternative possible sources for lineages ascribed a Sephardic Jewish origin, these proportions attest to a high level of religious conversion (whether voluntary or enforced), driven by historical episodes of social and religious intolerance, that ultimately led to the integration of descendants. In agreement with the historical record, analysis of haplotype sharing and diversity within specific haplogroups suggests that the Sephardic Jewish component is the more ancient. The geographical distribution of North African ancestry in the peninsula does not reflect the initial colonization and subsequent withdrawal and is likely to result from later enforced population movement—more marked in some regions than in others—plus the effects of genetic drift.
In the forensic medicine field, molecular autopsy is the post-mortem genetic analysis performed to attempt to unravel the cause of decease in cases remaining unexplained after a comprehensive ...forensic autopsy. This negative autopsy, classified as negative or non-conclusive, usually occurs in young population. In these cases, in which the cause of death is unascertained after a thorough autopsy, an underlying inherited arrhythmogenic syndrome is the main suspected cause of death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis, identifying a rare variant classified as potentially pathogenic in up to 25% of sudden death cases in young population. The first symptom of an inherited arrhythmogenic disease may be a malignant arrhythmia, and even sudden death. Early identification of a pathogenic genetic alteration associated with an inherited arrhythmogenic syndrome may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death in the victim's relatives, at risk despite being asymptomatic. The current main challenge is a proper genetic interpretation of variants identified and useful clinical translation. The implications of this personalized translational medicine are multifaceted, requiring the dedication of a specialized team, including forensic scientists, pathologists, cardiologists, pediatric cardiologists, and geneticists.
To determine whether single nucleotide polymorphisms (SNPs) of genes coding for matrix metalloproteinases (MMPs) and the prostaglandin F2α receptor gene (PTGFR) are related to a response to ...latanoprost in a white Spanish population of glaucomatous patients.
Case-control study.
One hundred twenty-four patients with open-angle glaucoma.
Genotyping was performed in 117 patients with primary open-angle glaucoma with a minimum treatment duration of 4 weeks. Candidate genes and individual polymorphisms were selected according to the effect on the mechanism of action of latanoprost. Multi-SNP haplotype analyses for associations also were tested.
Diurnal intraocular pressure reduction and genotyping of the SNPs in the MMPs and PTGFR.
The PTGFR SNPs were associated with positive (rs6686438, rs10786455) and negative (rs3753380, rs6672484, rs11578155) responses to latanoprost. Multiple testing found 2 genes, PTGFR and MMP-1, were related to refractoriness to latanoprost.
The SNPs of the PTGFR and MMP-1 genes may determine the latanoprost response in a white European Spanish population. This study identified 5 SNPs related to the latanoprost response; 1 SNP, rs3753380, already has been associated with a poor response to latanoprost in a healthy Japanese population. Latanoprost is a commonly used antiglaucomatous drug, and increased knowledge of its mechanism of action will lead to advances in pharmacogenetics.
In most societies, surnames are passed down from fathers to sons, just like the Y chromosome. It follows that, theoretically, men sharing the same surnames would also be expected to share related Y ...chromosomes. Previous investigations have explored such relationships, but so far, the only detailed studies that have been conducted are on samples from the British Isles. In order to provide additional insights into the correlation between surnames and Y chromosomes, we focused on the Spanish population by analysing Y chromosomes from 2121 male volunteers representing 37 surnames. The results suggest that the degree of coancestry within Spanish surnames is highly dependent on surname frequency, in overall agreement with British but not Irish surname studies. Furthermore, a reanalysis of comparative data for all three populations showed that Irish surnames have much greater and older surname descent clusters than Spanish and British ones, suggesting that Irish surnames may have considerably earlier origins than Spanish or British ones. Overall, despite closer geographical ties between Ireland and Britain, our analysis points to substantial similarities in surname origin and development between Britain and Spain, while possibly hinting at unique demographic or social events shaping Irish surname foundation and development.
Non-syndromic aortic disease (NSAD) is a frequently asymptomatic but potentially lethal disease characterised by familial cases of thoracic aortic aneurysms and dissections. This monogenic but ...genetically heterogeneous condition is primarily inherited as an autosomal dominant disorder with low penetrance and variable expression. Mutations in ACTA2, TGFBR1, TGFBR2, MYH11, SMAD3, MYLK, and FBN1 genes have been described but still, there are many unresolved familial cases.
The whole exome of two distantly related and affected members of a Spanish family with multiple cases of NSAD was analysed through 5500 SOLiD™ System for the identification of shared and putative pathogenic variants.
A new mutation termed c.C1042T:p.R348C (NM_001135599.2) was identified in TGFB2, a gene located in an evolutionary highly conserved region (Chr1: 218,519,577-218,617,961) that has been recently connected to this disease. The analysis of other family members using capillary sequencing confirmed cosegregation of the mutation with the disease and its incomplete penetrance.
The repeated implication of TGFB2 in the development of thoracic aortic aneurysms and dissections suggests that this gene should be considered during genetic diagnosis of this disease. An accurate diagnosis of affected individuals and additional family members at risk allows for a personalised and more efficient gene-based follow-up and treatment. Finally, the reiterative presence of common musculoskeletal and craniofacial additional features in patients with TGFB2 mutations suggests the existence of a new yet undefined connective tissue syndrome responsible for not only aortic dilation, but also for the other extracardiac alterations present in the affected patients.
•Genetic diagnosis of a non-syndromic aortic disease familial case was conducted.•The whole exome of two distant and affected relatives was sequenced.•One shared and putative pathogenic variant was identified in TGFB2.•TGFB2 should be regarded during genetic diagnosis of patients with aortic disease.•Non-syndromic diagnosis of these patients should be reconsidered.
Background
Acute thoracic aortic dissections and ruptures, the main life-threatening complications of the corresponding aneurysms, are an important cause of sudden cardiac death. Despite the ...usefulness of the molecular diagnosis of these conditions in the clinical setting, the corresponding forensic field remains largely unexplored. The main goal of this study was to explore and validate a new massive parallel sequencing candidate gene assay as a diagnostic tool for acute thoracic aortic dissection autopsy cases.
Materials and methods
Massive parallel sequencing of 22 thoracic aortic disease candidate genes performed in 17 cases of thoracic aortic dissection using
AmpliSeq
and
Ion Proton
technologies. Genetic variants were filtered by location, type, and frequency at the
Exome Aggregation Consortium
and an internal database and further classified based on the
American College of Medical Genetics and Genomics (ACMG) recommendations
published in 2015. All prioritized results were confirmed by traditional sequencing.
Results
From the total of 10 potentially pathogenic genetic variants identified in 7 out of the 17 initial samples, 2 of them were further classified as pathogenic, 2 as likely pathogenic, 1 as possibly benign, and the remaining 5 as variants of uncertain significance, reaching a molecular autopsy yield of 23%, approximately.
Conclusions
This massive parallel sequencing candidate gene approach proved useful for the molecular autopsy of aortic dissection sudden cardiac death cases and should therefore be progressively incorporated into the forensic field, being especially beneficial for the anticipated diagnosis and risk stratification of any other family member at risk of developing the same condition.
Molecular genetics of sudden cardiac death Rodríguez-Calvo, María Sol; Brion, María; Allegue, Catarina ...
Forensic science international,
11/2008, Volume:
182, Issue:
1
Journal Article
Peer reviewed
Abstract Sudden cardiac death (SCD) is one of the most common causes of death. An important number of sudden deaths, especially in the young, are due to genetic heart disorders, both with structural ...and arrhythmogenic abnormalities. In recent years, significant advances have been made in understanding the genetic basis of SCD. Identification of the genetic causes of sudden death is important because close relatives are also at potential risk of having a fatal cardiac condition. A comprehensive post-mortem investigation is vital to determine the cause and manner of death and provides the opportunity to assess the potential risk to the family after appropriate genetic counselling. In this paper, we present an update of the different genetic causes of sudden death, emphasizing their importance for the forensic pathologist due to his relevant role in the diagnosis and prevention of SCD.
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