Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations

Abstract

The aim of this study was to identify regions of the genome that harbor genes influencing inheritance of bicuspid aortic valve (BAV) and/or associated cardiovascular malformation (CVM). Aortic valve disease is an important clinical problem, which often results in valve replacement, the second most common cardiac surgery in the United States. In every age group, a majority of cases of valve disease involves a BAV. BAV is the most common CVM with a reported prevalence of 1-2%. Heritability studies indicate that BAV determination is almost entirely genetic. We used a family-based genome-wide linkage analysis with microsatellite markers. Parametric and nonparametric analyses were performed with the software GENEHUNTER and SOLAR (Sequential Oligogenic Linkage Analysis Routines). Thirty-eight families (353 subjects) with BAV and/or associated CVM were assessed. Each participant underwent a standardized echocardiographic examination. The highest LOD score, 3.8, occurred on chromosome 18q between markers D18S68 and D18S1161. Two other chromosomal regions, 5q15-21 (between D5S644 and D5S2027) and 13q33-qter (between D13S1265 and 13qter), exhibited suggestive evidence of linkage (LOD > 2.0). Further, two previously reported linkage peaks on 9q34 and 17q24 were replicated in family specific analyses. No significant X chromosome linkage peaks were identified. In this genome-wide scan we demonstrate for the first time, that BAV and/or associated CVM exhibit linkage to chromosomes 18q, 5q and 13q. These regions likely contain genes whose mutation results in BAV and/or associated CVM indicating their important role in valvulogenesis and cardiac development.

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

“…25 Interestingly, BAV has also exhibited linkage to chromosome 18q, where the GATA6 gene is located. 26 The above evidences suggested the potential role of GATA6 in the pathogenesis of BAV which, we believe, needs to be further explored in a large cohort of BAV patients.…”

Aortopathy pathophysiology features in patients with bicuspid aortic valve.

“…Преимущественное доминирование у мужчин (соотношение признака по полу -мужчины к женщинам 3:1), также как и сочетание ДАК с синдромом Тернера (признак 45X хромосомы) предполагает этиологию, связанную с Х хромосомой [21]. В последующих исследованиях были найдены области в хромосомах 5q,13q, 18q, которые имеют более сильную связь с признаком ДАК [22]. Мутации в гене NOTCH1 (9q34-35) ведут к патологии передачи информации, рисунок 1 -Схематическое изображение анатомических границ патологии, сочетанных с ДАК (розовым цветом отмечены структуры, подверженных патологии) которые ответственны не только за формирование ДАК, но и за ускоренный процесс кальцификации створок клапана (таблица 1) [23,24].…”

Clinical and Genetic Aspects of Bicuspid Aortic Valve: A Proposed Model for Family Screening Based on a Review of Literature

“…50 Based on studies in individual patients, linkage analysis in families and animal studies, several other genes and candidate loci have been implicated to be potentially involved in BAV. [51][52][53][54][55][56][57][58] These studies emphasize the genetic as well as phenotypic heterogeneity of BAV.…”

“…The results of these studies are summarized in Table 1. 26,28,41,42,54,61,[65][66][67][68][69] In 5.8-47.7% of the families BAV was shown to be familial (defined as BAV diagnosed in at least one first degree relative of the index patient). Of the screened first-degree relatives of BAV patients 1.8-11% was found to be affected with BAV.…”

“…3,13,20,24,[31][32][33] The other studies reported percentages of TAA in the first-degree TAV relatives of 3-4%. 54,[65][66][67][68] This is around population risk since 2.3% of the general population, by definition, is expected to have z scores >2. 28,70,71 In the large study by RobledoCarmona et al only mild aortic dilatation (<4 cm) at older age (>50 years), was observed among nine out of 270 first degree relatives with a TAV, comparable to the observations in the control cohort.…”