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Poloni, Giulia (2016) Arrhythmogenic Cardiomyopathy: identification of novel genes encoding for intercalated disc proteins by next-generation sequencing. [Tesi di dottorato]

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Abstract (inglese)

Introduction. Arrhythmogenic cardiomyopathy (ACM) is a predominantly genetically determined disease characterized by fibrofatty replacement which leads to right ventricular failure, arrhythmias, and sudden cardiac death (SCD). ACM is inherited as an autosomal dominant trait with incomplete penetrance. Advances in genetic technology have revealed substantial genetic heterogeneity: at least 15 independent loci and 13 disease genes have now been identified associated with the disease, with the large involvement of the genes encoding for desmosomal and area composita proteins. Since causative mutations in ACM genes have been detected in about 60% of probands, additional and still unknown disease-genes could be involved.
Aim of the study. This study aimed at detecting causative mutations underlying the disease expression in a cohort of 59 Italian unrelated index cases through a new targeted next generation sequencing (NGS) approach. Moreover, the identification of novel disease loci and genes in four families with recurrence of ACM was attempted by integrating different genetic approaches.
Methods. Three different NGS approaches have been applied: targeted gene panels (TGP), whole exome sequencing (WES), and whole genome sequencing (WGS). Two custom targeted gene panels, including 56 genes associated with different cardiomyopathies or 69 known and candidate ACM genes have been used to screen both familial and sporadic cases. Genetic analysis was extended to available family members to evaluate the segregation of each mutation identified in the index case. The whole exome of 11 subjects belonging to 4 families was sequenced. In one of these families (Family#6) also WGS in 3 subjects in addition to multipoint linkage analysis was performed.
Results. Targeted gene panels resulted a valuable tool for mutation screening in patients affected with ACM. At least a mutation was found in 15 out of 19 probands screened with the ‘Cardiomyopathies gene panel’. Moreover, by using the ‘ACM known and candidate genes panel’, a mutation in a candidate gene has been identified in 40.6% of probands negative for mutations in known-disease genes. Two novel missense variants in TJP1 gene (p.R265W, p.Y669C), encoding for protein ZO-1 and two in CDH2 gene (p.E493G, p.V491G), encoding for N-cadherin resulted of particular interest, other than a stop mutation in TP63 gene (p.R266*). Both TJP1 mutations affected highly conserved amino acid residues and in silico analysis of p.Y669C mutation, which segregates within the proband’s family, showed its predicted damaging effect into the protein structure.
WES analysis allowed to identify a pathogenic mutation in DSP gene (p.Q1297*) not previously detected by dHPLC in Family#3, and two putative TTN mutations (p.R32573C and p.L32198M) that segregate in Family#4 and Family#5. In Family#5, a rare stop mutation in a candidate gene (CMYA5, p.K3597*) was also identified.
In Family #6, a multi-step approach was applied. The availability of many affected and unaffected family members allowed to perform linkage analysis in an ‘affected only’ approach. The analysis pointed out the presence of two regions with positive pLOD score values on chromosome 19p13.3 and 11q21. The first corresponded to a 7cM region and was shared by all the affected subjects, but one. The 3cM region on chromosome 11q21 segregated in all the affected subjects exception made for two, who carried a PKP2 splice site variant (c.2578-3 T>C). WES performed in 4 patients of the family failed to identified a possible shared pathogenic mutation neither inside the critical regions, nor in the whole exome. These results were confirmed with WGS performed in 2 affected and a healthy individual. Moreover WGS pointed out the presence of a huge amount of complex variants located in repetitive intronic or intragenic regions.
Discussion. The identification of disease-causing mutations facilitates timely diagnosis, allows the prevention of complications and determines the potential risk in close relatives of a proband. For hereditary cardiomyopathies, as well as for most mendelian diseases, in the last ten years NGS technology improved this process allowing to parallel sequence a large amount of genes in a time and cost-efficient manner. Since mutations in the most index cases sequenced by using a targeted gene panel have been detected, it resulted a valid approach not only for genetic testing but also to identify putative novel disease genes. In the present study, novel mutations in genes encoding for intercalated disc proteins (TJP1, CDH2) have been identified, confirming the idea that ACM has to be considered a ‘junctional disease’ rather than only a ‘desmosomal disease’.
Despite TGP remains the most commonly used approach for hereditary cardiomyopathies, WES, applied in familial ACM cases, allowed to identify novel variants in candidate genes that would be not detected with TGP and could have a possible pathogenic role or a modifier effect in the phenotypic expression. Finally, even though WGS didn’t allow to make a genotype-phenotype correlation in Family #6, the huge amount of data produced represent permanent data that could be re-analysed in the future with new insights and the discovery of novel disease genes.

Abstract (italiano)

Introduzione. La cardiomiopatia aritmogena (ACM) è una patologia ereditaria del muscolo cardiaco, caratterizzata da una progressiva sostituzione adiposa o fibroadiposa a carico prevalentemente del miocardio del ventricolo destro. Dal punto di vista clinico, è una patologia eterogenea con ampia variabilità clinica inter- ed intra- familiare; presenta infatti sia forme completamente asintomatiche sia forme molto gravi con rischio di morte improvvisa. Questa patologia, geneticamente eterogenea, è trasmessa come carattere autosomico dominante a penetranza incompleta ed espressività variabile. Ad oggi 15 loci e 13 geni sono stati associati alla malattia, di cui gran parte codificano per proteine desmosomali e proteine della cosiddetta area composita dei dischi intercalari. Poiché sono state identificate mutazioni causative in geni noti sono nel 60% dei casi, altri geni, non ancora identificati, potrebbero essere coinvolti nella comparsa del fenotipo patologico.
Scopo della ricerca. Nello studio descritto nella presente tesi, il DNA di 59 casi indice è stato analizzato attraverso due diversi pannelli di geni tramite sequenziamento di nuova generazione (NGS). Inoltre, in quattro famiglie con ricorrenza di casi di ACM, in cui non sono state identificate mutazioni nei geni desmosomali, sono state integrate diverse tecniche allo scopo di identificare nuovi loci e geni malattia.
Metodi. Nell’ambito del sequenziamento di nuova generazione (NGS) tre diversi approcci sono stati utilizzati: il sequenziamento di pannelli di geni target (TGP), il sequenziamento dell’intero esoma (WES) e il sequenziamento dell’intero genoma. Due sono i pannelli di geni considerati, uno comprendente 56 geni associati a diverse cardiomiopatie, l’altro comprendente 69 geni, tra cui i 13 geni associati alla cariomiopatia aritmogena e 56 geni candidati. L’analisi genetica è stata poi estesa ai familiari dei probandi, ove disponibili, per valutare la segregazione delle mutazioni identificate. L’intero esoma è stato poi sequenziato in 11 soggetti appartenenti a 4 diverse famiglie. Infine, in una di queste famiglie (Famiglia#6) è stata eseguita un’analisi di linkage ed è stato sequenziato l’intero genoma di tre soggetti.
Risultati. L’utilizzo dei pannelli di geni target si è rivelato una buona strategia per lo screening di mutazioni in pazienti affetti da ACM: almeno una mutazione è stata trovata in 15 probandi su un totale di 19 analizzati con il pannello di geni associati a diverse cardiomiopatie; inoltre, è stata identificata una mutazione in uno dei geni candidati nel 40.6% dei probandi sequenziati con il secondo pannello e risultati negativi per mutazioni nei geni noti. Tra queste mutazioni, risultano di particolare interesse 2 nuove mutazioni missenso localizzate nel gene TJP1 (p.R265W, p.Y669C), 2 mutazioni nel gene che codifica per l’N-caderina (CDH2, p.E493G, p.V491G) e una mutazione di stop nel gene TP63 (p.R266*). Entrambe le mutazioni di TJP1 riguardano aminoacidi altamente conservati, inoltre un’analisi in silico degli effetti della mutazione p.Y669C, che segrega all’interno della famiglia, evidenzia un riarrangiamento della struttura proteica della proteina che riporta la mutazione rispetto alla proteina wild-type.
L’analisi dell’esoma nella Famiglia#3 ha permesso di identificare una mutazione patogena di stop nel gene DSP, che non era stato possibile individuare al precedente screening tramite dHPLC. Inoltre, tale approccio ha permesso di identificare due putative mutazioni nel gene TTN (p.R32573C and p.L32198M) che segregano nelle Famiglie #4 e #5, rispettivamente. Nella Famiglia #5 inoltre è stata identificata una rara mutazione di stop in un gene candidato (CMYA5, p.K3597*). Per lo studio della Famiglia#6, invece, sono stati utilizzati diversi approcci. Data la disponibilità di molti soggetti affetti e sani appartenenti alla famiglia, in seguito alla genotipizzazione degli stessi, è stata eseguita un’analisi di linkage. L’analisi ha evidenziato la presenza di due loci che riportano valori di lod score positivi a livello del cromosoma 19p13.3 e del cromosoma 11q21. Il primo locus corrisponde ad una regione di 7 cM ed è condiviso da tutti i soggetti affetti della famiglia, eccetto uno. La regione di 3cM nel cromosoma 11q21 invece segrega in tutti i soggetti affetti ad eccezione di due, che portano una mutazione in un sito di splicing del gene PKP2 (c.2578-3 T>C). Il sequenziamento dell’esoma in 4 soggetti affetti della famiglia non ha permesso di identificare nuove mutazioni condivise né all’interno delle due regioni critiche, né all’interno dell’intero esoma. Tali risultati sono stati confermati dal sequenziamento del genoma effettuato in due affetti e un soggetto sano della famiglia. Il sequenziamento del genoma ha inoltre messo in luce la presenza di un’enorme quantità di varianti complesse localizzate in regioni introniche o intrageniche.
Discussione. L’identificazione di mutazioni causative nella cardiomiopatia aritmogena facilita la diagnosi tempestiva, permette di prevenire eventuali complicazioni e determina il rischio di sviluppare la malattia nei familiari di un soggetto affetto. Per le cardiomiopatie ereditarie, come per la maggior parte delle malattie mendeliane, negli ultimi 10 anni le tecniche NGS hanno apportato grossi miglioramenti nel processo di identificazione di mutazioni, permettendo di sequenziare una grande quantità di geni parallelamente, in modo più rapido e meno costoso. In questo studio, dal momento che sono state identificate mutazioni nella maggior parte di probandi analizzati, l’utilizzo di pannelli di geni target si è dimostrato un valido approccio non solo per un test genetico ma anche per l’identificazione di nuovi geni malattia. Sono state infatti identificate nuove mutazioni in geni che codificano per proteine dei dischi intercalari dei cardiomiociti, confermando l’idea che l’ACM deve essere considerata una ‘malattia delle giunzioni’ piuttosto che una ‘malattia dei desmosomi’.
Nonostante l’utilizzo di pannelli di geni target rimanga l’approccio più comunemente usato nella ricerca di mutazioni nelle cardiomiopatie ereditarie, il sequenziamento dell’intero esoma, applicato in questo studio solo a casi familiari, ha permesso di identificare varianti in geni candidati non inclusi nei pannelli di geni e che potrebbero avere un ruolo nell'espressione del fenotipo patologico. Infine, nonostante il sequenziamento del genoma nella Famiglia#6 non abbia permesso al momento di stabilire una correlazione tra genotipo e fenotipo al momento, la mole di dati prodotti potrà essere rianalizzata in futuro alla luce di nuovi geni annotati e nuovi geni malattia identificati.

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Tipo di EPrint:Tesi di dottorato
Relatore:Rampazzo, Alessandra
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE CARDIOVASCOLARI
Data di deposito della tesi:29 Gennaio 2016
Anno di Pubblicazione:31 Gennaio 2016
Parole chiave (italiano / inglese):cardiomiopatia/cardiomyopathy; morte improvvisa/sudden death; sequenziamento di nuova generazione/next generation sequencing; genetica molecolare/molecular genetics; dischi intercalari/intercalated discs
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/18 Genetica
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:9054
Depositato il:21 Ott 2016 15:46
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