Thoracic aortic aneurysms (TAA) are an important cause of mortality and morbidity in Eastern countries. Among the main causes of TAA, there are valvular aortic diseases and connective tissue disorders, both main object of this research project through the study of bicuspid aortic valve (BAV) and Loeys- Dietz Syndrome (LDS). The first focus of this research is on the genetic study of non syndromic BAV-TAA. We recruited 20 patients and 77 first degree relatives and performed Sanger sequencing analysis of the candidate gene ACTA2, followed by a targeted panel analysis of known genes involved in BAV, and whole exome sequencing analysis (WES) in familiar cases. ACTA2 analysis and the targeted panel revealed no known mutations in the 20 patients, suggesting no major role of ACTA2 in BAV-TAA disorder. WES analysis was performed in 5 families with 2 or more relatives with BAV and TAA. Analytic study approach of variants filtered and annotated revealed no strong candidate genes, suggesting new strategies, such as whole genome sequencing, to identify molecular mechanism of BAV-TAA. The second focus of this research is on genotype-phenotype correlations in LDS. Systematic research of medical literature was performed along with collection of cases of three International Centers involved in LDS diagnosis. We built a web database LOVD v.3 (Leiden Open Variation Database) where we collected 595 cases. Mutational hot-spots were observed without a strong evidence of phenotypic correlation; mutations are mainly missense; de novo cases are about 60%; very mild differences in phenotype associate to different gene were observed. Database details, both molecular and clinical data, are open and of interest for LDS Diagnostic Centers; the LDS-LOVD will be constantly updated and new centers will be involved.
Gli aneurismi dell’aorta toracica (AAT) rappresentano una significativa causa di mortalità e morbilità nella popolazione dei paesi occidentali. Tra le cause di AAT vi sono anche patologie valvolari cardiache e del connettivo, entrambi oggetto di questa ricerca attraverso lo studio della valvola aortica bicuspide (BAV) e della sindrome di Loeys-Dietz (LDS). La prima parte della ricerca è stata dedicata allo studio delle basi genetiche di BAV-AAT non sindromico. Sono stati reclutati 20 pazienti e 77 familiari di I grado ed è stata eseguita analisi Sanger del gene candidato ACTA2, seguita da analisi di pannelli di geni coinvolti in BAV e di whole exome sequencing (WES). Le analisi di ACTA2 e del pannello genico sono risultate negative nei 20 pazienti, suggerendo assenza di coinvolgimento maggiore di ACTA2 in BAV-AAT. Le analisi WES sono state effettuate in 5 famiglie con 2 o più familiari con BAV e AAT. L’approccio analitico allo studio delle varianti non ha individuato forti geni candidati suggerendo nuove vie da percorrere, quali whole genome sequencing, per riuscire ad identificare i meccanismi molecolare alla base di BAV-AAT. La seconda parte della ricerca è stata dedicata allo studio della relazione genotipo-fenotipo in LDS. È stata eseguita una ricerca sistematica della letteratura medica ed è stata raccolta la casistica di tre Centri Internazionali coinvolti nella diagnostica di LDS. È stato costruito un database dedicato su piattaforma web LOVD v.3 (Leiden Open Variation Database) in cui sono stati raccolti 595 casi. Sono emersi degli hot-spot mutazionali nei singoli geni senza una forte evidenza di correlazione fenotipica; le mutazioni sono principalmente missenso; i casi de novo sono circa il 60%; sono state osservate lievi differenze fenotipiche associate ai diversi geni. I dettagli sono visibili e fruibili sia nei dati molecolari che clinici a beneficio dei Centri Diagnostici in LDS, il database sarà costantemente aggiornato e nuovi centri saranno coinvolti.
Genetica delle aortopatie toraciche / Tortora, Giada. - (2018 Mar 13).
Genetica delle aortopatie toraciche
TORTORA, GIADA
2018-03-13
Abstract
Thoracic aortic aneurysms (TAA) are an important cause of mortality and morbidity in Eastern countries. Among the main causes of TAA, there are valvular aortic diseases and connective tissue disorders, both main object of this research project through the study of bicuspid aortic valve (BAV) and Loeys- Dietz Syndrome (LDS). The first focus of this research is on the genetic study of non syndromic BAV-TAA. We recruited 20 patients and 77 first degree relatives and performed Sanger sequencing analysis of the candidate gene ACTA2, followed by a targeted panel analysis of known genes involved in BAV, and whole exome sequencing analysis (WES) in familiar cases. ACTA2 analysis and the targeted panel revealed no known mutations in the 20 patients, suggesting no major role of ACTA2 in BAV-TAA disorder. WES analysis was performed in 5 families with 2 or more relatives with BAV and TAA. Analytic study approach of variants filtered and annotated revealed no strong candidate genes, suggesting new strategies, such as whole genome sequencing, to identify molecular mechanism of BAV-TAA. The second focus of this research is on genotype-phenotype correlations in LDS. Systematic research of medical literature was performed along with collection of cases of three International Centers involved in LDS diagnosis. We built a web database LOVD v.3 (Leiden Open Variation Database) where we collected 595 cases. Mutational hot-spots were observed without a strong evidence of phenotypic correlation; mutations are mainly missense; de novo cases are about 60%; very mild differences in phenotype associate to different gene were observed. Database details, both molecular and clinical data, are open and of interest for LDS Diagnostic Centers; the LDS-LOVD will be constantly updated and new centers will be involved.File | Dimensione | Formato | |
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