The genetic background of Brugada Syndrome is proving to be incredibly complex. In this setting, studying population isolates, characterized by high genetic and environmental homogeneity, is expected to provide new data on the pathogenesis of the disease and refine genotype-phenotype correlations. In our analysis we adopted a haplotype-based approach and used 28 Single Nucleotide Polymorphism to reconstruct haplotype in 201 subjects, in order to investigate the origin and significance of two SCN5A genetic variants in a population originating from a small area in Southern Italy. One SCN5A variant (p.Gln1118Ter) was identified in 5 probands and was found to be associated to a core haplotype with a low frequency in the general populatipn. This variant was accompanied by a phenotype characterized by Brugada Syndrome, sudden cardiac death and cardiac conduction deficits. Thanks to the reconstruction of familial pedigrees with a common geographic origin and estimates of mutational age dating back 76 generations, p. Gln1118Ter was recognized as a founder mutation resulting in a very severe Brugada Syndrome phenotype.
LE COMPLESSE BASI GENETICHE DELLA SINDROME DI BRUGADA: RECENTI SVILUPPI A PARTIRE DALLA SCOPERTA DI UNA NUOVA MUTAZIONE FOUNDER. Il background genetico della Sindrome di Brugada si sta rivelando incredibilmente complesso. In questo contesto, lo studio di isolati di popolazione, caratterizzati da elevata omogeneità genetica e ambientale, dovrebbe fornire nuovi dati sulla patogenesi della malattia e affinare le correlazioni genotipo-fenotipo. Nella nostra analisi abbiamo adottato un approccio “haplotype-based” e utilizzato 28 polimorfismi a singolo nucleotide (single-nucleotide polymorphism, o SNP) per ricostruire l'aplotipo in 201 soggetti, al fine di indagare l'origine e il significato di due varianti genetiche di SCN5A in una popolazione originaria di una ristretta area del Sud Italia. Una variante di SCN5A (p.Gln1118Ter) è stata identificata in 5 probandi ed è risultata associata a un aplotipo con una bassa frequenza nella popolazione generale. Questa variante è accompagnata da un fenotipo caratterizzato da sindrome di Brugada, morte cardiaca improvvisa e deficit di conduzione cardiaca. Grazie alla ricostruzione di pedigree familiari con una comune origine geografica e una stima di età mutazionale risalente a 76 generazioni, p. Gln1118Ter è stata riconosciuta come mutazione “founder” condizionante un fenotipo particolarmente severo di sindrome di Brugada.
THE COMPLEX GENETICS OF BRUGADA SYNDROME: INSIGHTS FROM THE DISCOVERY OF A NOVEL FOUNDER MUTATION
GRIFFINI, GIULIA
2020/2021
Abstract
The genetic background of Brugada Syndrome is proving to be incredibly complex. In this setting, studying population isolates, characterized by high genetic and environmental homogeneity, is expected to provide new data on the pathogenesis of the disease and refine genotype-phenotype correlations. In our analysis we adopted a haplotype-based approach and used 28 Single Nucleotide Polymorphism to reconstruct haplotype in 201 subjects, in order to investigate the origin and significance of two SCN5A genetic variants in a population originating from a small area in Southern Italy. One SCN5A variant (p.Gln1118Ter) was identified in 5 probands and was found to be associated to a core haplotype with a low frequency in the general populatipn. This variant was accompanied by a phenotype characterized by Brugada Syndrome, sudden cardiac death and cardiac conduction deficits. Thanks to the reconstruction of familial pedigrees with a common geographic origin and estimates of mutational age dating back 76 generations, p. Gln1118Ter was recognized as a founder mutation resulting in a very severe Brugada Syndrome phenotype.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/13282