HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN

Loeys-dietz syndrome; Marfan syndrome; Thoracic aortic aneurysmSíndrome de Loeys-dietz; Síndrome de Marfan; Aneurisma aòrtic toràcicSíndrome de loeys-dietz; Síndrome de Marfan; Aneurisma aórtico torácicoHeritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic. They may result from genetic defects. Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism. Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out. This document is an expert opinion reflecting strategies put forward by medical experts and patient representatives involved in the HTAD Rare Disease Working Group of VASCERN. It aims to provide a patient pathway that improves patient care by diminishing time to diagnosis, facilitating the establishment of a correct diagnosis using molecular genetics when possible, excluding the diagnosis in unaffected persons through appropriate family screening and avoiding overuse of resources. It is being recommended that patients are referred to an expert centre for further evaluation if they meet at least one of the following criteria: (1) thoracic aortic dissection (3.5 or 2.5–3.5 if non-hypertensive or hypertensive and 3), (3) family history of HTAD with/without a pathogenic variant in a gene linked to HTAD, (4) ectopia lentis without other obvious explanation and (5) a systemic score of >5 in adults and >3 in children. Aortic imaging primarily relies on transthoracic echocardiography with magnetic resonance imaging or computed tomography as needed. Genetic testing should be considered in those with a high suspicion of underlying genetic aortopathy. Though panels vary among centers, for patients with thoracic aortic aneurysm or dissection or systemic features these should include genes with a definitive or strong association to HTAD. Genetic cascade screening and serial aortic imaging should be considered for family screening and follow-up. In conclusion, the implementation of these strategies should help standardise the diagnostic work-up and follow-up of patients with suspected HTAD and the screening of their relatives.CHAFEA Specific Grant Agreement for Year 1 HP-ERN-SGA-2016 10 Project n° 769036 (from March 2017 to February 2018) 11 - CHAFEA Specific Grant Agreement for Year 2 HP-ERN-SGA-2017 12 Project n° 811609 (from March 2018 to February 2019) 13 - CHAFEA Specific Grant Agreement for Year 3 to 5 HP-ERN-SGA-2018 14 Project n° 847081 (from March 2019 to February 2022)

Y-chromosomal analysis of Greek Cypriots reveals a primarily common pre-Ottoman paternal ancestry with Turkish Cypriots

Genetics can provide invaluable information on the ancestry of the current inhabitants of Cyprus. A Y-chromosome analysis was performed to (i) determine paternal ancestry among the Greek Cypriot (GCy) community in the context of the Central and Eastern Mediterranean and the Near East; and (ii) identify genetic similarities and differences between Greek Cypriots (GCy) and Turkish Cypriots (TCy). Our haplotype-based analysis has revealed that GCy and TCy patrilineages derive primarily from a single gene pool and show very close genetic affinity (low genetic differentiation) to Calabrian Italian and Lebanese patrilineages. In terms of more recent (past millennium) ancestry, as indicated by Y-haplotype sharing, GCy and TCy share much more haplotypes between them than with any surrounding population (7–8% of total haplotypes shared), while TCy also share around 3% of haplotypes with mainland Turks, and to a lesser extent with North Africans. In terms of Y-haplogroup frequencies, again GCy and TCy show very similar distributions, with the predominant haplogroups in both being J2a-M410, E-M78, and G2-P287. Overall, GCy also have a similar Y-haplogroup distribution to non-Turkic Anatolian and Southwest Caucasian populations, as well as Cretan Greeks. TCy show a slight shift towards Turkish populations, due to the presence of Eastern Eurasian (some of which of possible Ottoman origin) Y-haplogroups. Overall, the Y-chromosome analysis performed, using both Y-STR haplotype and binary Y-haplogroup data puts Cypriot in the middle of a genetic continuum stretching from the Levant to Southeast Europe and reveals that despite some differences in haplotype sharing and haplogroup structure, Greek Cypriots and Turkish Cypriots share primarily a common pre-Ottoman paternal ancestry

Gene polymorphisms, gene expression and atherosclerotic plaques

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Identification of novel splice mutation in SMAD3 in two Cypriot families with nonsyndromic thoracic aortic aneurysm. Two case reports

Abstract Background Thoracic aortic aneurysm and dissection (TAA/D) represents a potentially lethal disease group characterized by an increased risk of dissection or rupture. Only a small percentage (approximately 30%) of individuals with nonsyndromic familial TAA/D have a pathogenic variant in one of the genes that have been found to be associated with the disease. Methods A targeted sequencing panel and direct sequencing approach were used to identify causative mutations in the index patients and other family members. Results In this study we report two apparently unrelated Cypriot families with nonsyndromic familial TAA/D. The proband A is a female patient diagnosed with TAA/D and intracranial aneurysm and opted for an elective intervention. The proband B is a male patient who was diagnosed with TAA/D and underwent cardiac surgery. Sequencing analysis identified a novel splice site variant (c.871+1G>A) in SMAD3 which is shown to be associated with the disease. Analysis of mRNA from the patient's tissue confirmed aberrant splicing and exon 6 skipping. Conclusion Our findings expand the mutation spectrum of variants that have been shown to be associated with nonsyndromic familial TAA/D. This study demonstrates the importance of a comprehensive clinical and genetic evaluation aiming at early diagnosis and intervention

Primer sequences which were used for Sanger Sequencing.

A combination of a forward and reverse primers from the table were used for a targeted sequencing for each hypervariable segment. (XLSX)</p

Comprehensive statistical analysis between Cyprus and countries of interest.

The genetic distances were calculated between Cypriots and countries of interest using the Arlequin software, providing information regarding their genetic differentiation. (XLSX)</p

Number and percentage of individuals from Southeast Europe, the Near East and North Africa that share haplotypes^a with Cypriots.

<p>Number and percentage of individuals from Southeast Europe, the Near East and North Africa that share haplotypes<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179474#t001fn001" target="_blank">^a</a> with Cypriots.</p