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Calore, Chiara (2011) Genotype-phenotype correlations and genetic family screening in hypertrophic cardiomyopathy. [Tesi di dottorato]

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Abstract (inglese)

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Clinical presentation is heterogeneous, outcome ranging from benign asymptomatic forms to more malignant expressions resulting in sudden or heart failure death. To date, more than 450 mutations have been reported in genes encoding sarcomeric proteins, proteins of the Z-disc, intercalated discs and in genes involved in cardiac metabolism. DNA testing is helpful for confirming diagnosis in ambiguous situations, can give some prognostic information and represents the gold standard for preclinical diagnosis in family members. However, mutation screening in HCM allows positive results in a small percentage of probands and is expensive and time-consuming.
Aim of this study was to identify pathogenic mutations in the most common HCM related genes and to correlate molecular defect with clinical-morphological phenotypic pattern in a large cohort of HCM probands from a single centre. Since the mutation in the index case has been identified, a cascade screening has been performed in the first degree family members searching for carriers.
Genetic screening for the 4 most commonly HCM-related sarcomeric genes (i.e. MYBPC3, MYH7, TNNT2, TNNI3) was performed by denaturing high performance liquid chromatography (DHPLC) and direct sequencing in 83 HCM index-cases from large and/or “malignant” families. A subgroup of 30 probands underwent more extensive mutation screening by 12 genes (i.e. MYH7, MYBPC3, MYL2, MYL3, TNNT2, TNNI3, TNNC1, TPM1, ACTC, CSRP3, PLN and PRKAG2) array-based DNA resequencing assay. If the mutations found were novel, these were searched in a healthy control population to rule out the possibility that they represent single nucleotide polymorphisms (SNPs).
Including both screening methods, our population consisted of 99 index cases (age at diagnosis 31±17 years, age at last control 45±17 years, 70% males, 65% familial cases, 38% with obstruction). Twenty-seven pathogenic HCM-causing mutations were found in 30 probands (30%). Percentage of mutation positive patients was not different in probands with HCM family history (21/64 probands, 33%) versus sporadic cases (9/35 probands, 26%; p=0.46), and irrespective of the screening method used (25/83 probands, 30%, by DHPLC and direct sequencing vs 8/30 probands, 27%, by DNA resequencing array; p=0.72). In 14 index-cases screened both by DHPLC and DNA resequencing array, there was agreement between the two different screening methods (3 mutations in 3 patients found by both methods, and just an intronic mutation “missed” by DNA resequencing array). Genes more frequently involved were MYH7 coding for beta-myosin heavy chain (11 mutations in 11 patients) and MYBPC3 for cardiac myosin-binding protein C (8 mutations in 12 patients). In a minority of probands HCM-causing genes were TNNI3, TNNT2 and MYL3, respectively in 4, 3 and one patients. Two patients had double mutation in compound heterozygous.
Wide heterogeneity in clinical presentation and evolution was present in spite of genotype characterization, but when multiple mutations were detected, they were associated with particularly severe phenotype.
Fifty-one members from 16 different families were screened for the mutation(s) found in their family proband and 23 (45%) resulted carriers. Eight carriers had phenotypic expression fulfilling diagnostic criteria for HCM (i.e. maximal left ventricular wall thickness, MLVWT ≥ 13 mm), whereas 10 had only minor signs suggestive of HCM (such as ECG abnormalities, MLVWT=12-13 mm, abnormal left ventricular filling pattern at echo-Doppler), and 5 were healthy carriers. Tissue Doppler Imaging seemed to be useful for preclinical diagnosis, but a multiparametric evaluation is needed to identify mutation carriers before phenotypic expression of HCM.
Nowadays, mutation screening is becoming part of diagnostic and clinical management of HCM patients and family members. The spectrum of HCM-associated genes has moved outside the myofilaments of the sarcomere to encompass additional subgroups of proteins involved in the pathogenesis of HCM.
Mutation carriers without HCM phenotype represent a new subgroup of patients at risk for developing disease, whose clinical and prognostic profile remains unresolved, but of particular interest as possible target for preventive therapeutic strategies that can change the natural history of this disease.

Abstract (italiano)

La cardiomiopatia ipertrofica (CMI) rappresenta la più frequente malattia cardiaca geneticamente determinata. È caratterizzata da un decorso clinico estremamente eterogeneo, che può variare da forme benigne ed asintomatiche a quadri particolarmente severi culminanti con morte improvvisa o per insufficienza cardiaca.
Fino ad oggi sono state identificate più di 450 diverse mutazioni a carico di oltre 20 geni codificanti non solo proteine del sarcomero, ma anche altre strutture cellulari quali il disco Z e i dischi intercari o geni implicati nel metabolismo cardiaco.
L’analisi genetica è un importante strumento diagnostico nelle situazioni dubbie, può dare talora indicazioni prognostiche, ma soprattutto consente di porre una diagnosi preclinica nei familiari di probandi affetti da CMI. Tuttavia essa consente di ottenere dei risultati conclusivi sono in una limitata percentuale di soggetti e rappresenta una metodica costosa, laboriosa ed ancora prerogativa di pochi centri specializzati.
Lo scopo di questo studio è stata l’identificazione di mutazioni patogene nei geni sarcomerici più frequentemente implicati nella CMI e la ricerca di correlazioni genotipo-fenotipo in un’ampia popolazione di pazienti con CMI seguiti presso l’ambulatorio specialistico della Clinica Cardiologica dell’Università di Padova. Una volta individuata la mutazione patogena nel probando, questa è stata ricercata nei familiari di primo grado al fine di consentire una diagnosi precoce e di programmare un adeguato follow-up clinico.
Data l’impossibilità di sottoporre sistematicamente l’intera popolazione seguita presso il nostro ambulatorio specialistico a tale indagine, si è deciso di procedere con un approccio razionale “a cascata” selezionando 83 casi-indice con forme fenotipicamente più severe o appartenenti a grandi famiglie in cui si erano verificati numerosi eventi maggiori e sottoponendo questi ad analisi genetica per screening di mutazioni nei 4 geni sarcomerici noti dalla letteratura essere i più frequentemente implicati nella CMI (MYBPC3, MYH7, TNNT2, TNNI3) mediante denaturing high performance liquid chromatography (DHPLC) e sequenziamento diretto. Un sottogruppo di 30 probandi è stato sottoposto ad analisi per ricerca di mutazioni in 12 geni sarcomerici e non (MYH7, MYBPC3, MYL2, MYL3, TNNT2, TNNI3, TNNC1, TPM1, ACTC, CSRP3, PLN e PRKAG2) mediante tecnica di DNA resequencing array. Qualora la mutazione trovata non fosse già nota in letteratura, questa è stata testata in una popolazione di controllo di soggetti sani, per confermare che non si trattasse di un polimorfismo.
Comprendendo entrambi i metodi di screening la nostra popolazione è risultata composta da 99 casi-indice (età media alla diagnosi 31±17 anni, età all’ultimo controllo 45±17 anni, 70% maschi, 65% con familiarità per CMI, 38% forme ostruttive). Sono state identificate 27 mutazioni patogene in 30 probandi (30%). La percentuale di probandi con mutazione è risultata non variare a seconda del metodo di screening utilizzato (25/83 probandi, 30%, identificati mediante DHPLC e sequenziamento diretto contro 8/30 probandi, 27%, mediante DNA resequencing array, p=0,72), né sulla base della storia familiare di CMI (21/64, 33%, nelle forme familiari, contro 9/35, 26%, nei casi sporadici, p=0,46). Dei 14 probandi indagati con entrambe le tecniche, in 3 casi le stesse mutazioni sono state identificate con entrambi i metodi, mostrando una buona concordanza diagnostica. Una sola mutazione in una regione intronica è stata identifica al DHPLC, ma “mancata” al DNA resequencing array. I geni più frequentemente implicati sono risultati MYH7 codificante la catena pesante della beta-miosina con 11 mutazioni in 11 probandi e MYBPC3 codificante la proteina C legante la miosina con 8 mutazioni in 12 probandi. Meno frequentemente sono state riscontrate mutazioni nei geni per le troponine cardiache I e T (rispettivamente in 4 e 3 pazienti) ed in un caso è stata riscontrata una mutazione nel gene MYL3 codificante la catena leggera essenziale della miosina. In due pazienti erano presenti doppie mutazioni.
Pazienti con mutazioni a carico dello stesso gene presentavano quadri clinici e decorso estremamente variabile, particolarmente severo nei pazienti con mutazioni multiple.
In 51 familiari, provenienti da 16 famiglie, è stata ricercata la mutazione patogena trovata nel probando, e di questi 23 (45%) sono risultati portatori. Mentre in 8 pazienti alla presenza di mutazione corrispondeva espressione clinica di malattia, in 5 non vi erano segni di CMI e nei restanti 10 solamente alterazioni minori non ancora diagnostiche (alterazioni aspecifiche dell’ECG, spessore parietale del ventricolo sinistro tra 12 e 13 mm, alterato rilasciamento all’eco-Doppler). L’analisi con Doppler Tissutale si è dimostrata sensibile nell’identificazione di anomalie precoci nei portatori di mutazioni e, se inserita in un approccio diagnostico multiparametrico, potrebbe consentire una diagnosi preclinica.
In conclusione, sebbene rappresenti un’indagine costosa e che consente l’identificazione di mutazioni patogene solo in una percentuale di pazienti variabile (circa 30%) l’analisi genetica è entrata a far parte del percorso clinico-diagnostico della cardiomiopatia ipertrofica. Il numero di geni candidati e di mutazioni è in continuo sviluppo comprendendo anche numerosi geni non-sarcomerici.
Ampia variabilità clinica e fenotipica è presente nei pazienti con singola mutazione, mentre i pazienti con doppie mutazioni vanno incontro ad un decorso particolarmente severo.
Lo screening genetico nei familiari per la ricerca della mutazione identificata nel probando rappresenta il gold-standard per la diagnosi precoce e può guidare il follow-up clinico (stretta sorveglianza clinica per i portatori, rassicurazione e controlli dilazionati nei negativi). Il sottogruppo di portatori sani, il cui decorso clinico rimane ancora da chiarire, rappresenta inoltre un’interessante popolazione per studiare fenomeni precoci di comparsa della malattia ed eventuali strategie preventive.

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Tipo di EPrint:Tesi di dottorato
Relatore:Melacini, Paola
Dottorato (corsi e scuole):Ciclo 23 > Scuole per il 23simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE CARDIOVASCOLARI
Data di deposito della tesi:18 Giugno 2011
Anno di Pubblicazione:18 Giugno 2011
Parole chiave (italiano / inglese):Cardiomiopatia ipertrofica /hypertrophic cardiomyopathy; analisi genetica/genetic screening
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/11 Malattie dell'apparato cardiovascolare
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Dipartimenti > pre 2012 - Dipartimento di Scienze Medico Diagnostiche e Terapie Speciali
Codice ID:4212
Depositato il:22 Giu 2012 09:41
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Bibliografia

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