RESUMO
The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect. Using identity-by-descent (IBD) networks, we estimate the broad- and fine-scale population ancestry of risk allele carriers and their relatives. Analysis of ancestral migration routes reveals ancestors who inhabited Denmark in the 1700s, migrated to the Northeastern United States in the early 1800s, and traveled across the Midwest to arrive in Utah in the late 1800s. IBD/coalescent-based allele dating analysis reveals a relatively recent origin of the AF risk allele (~5000 years). Thus, our approach broadens the scope of study for disease susceptibility alleles to the context of human migration and ancestral origins.
Assuntos
Fibrilação Atrial/genética , Predisposição Genética para Doença/genética , Canal de Potássio KCNQ1/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Potenciais de Ação , Alelos , Dinamarca , Emigrantes e Imigrantes , Feminino , Genótipo , Geografia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Linhagem , Fatores de Risco , UtahRESUMO
BACKGROUND: Pathogenic variants in the L-type Ca2+ channel gene CACNA1C cause a multi-system disorder that includes severe long QT syndrome (LQTS), congenital heart disease, dysmorphic facial features, syndactyly, abnormal immune function, and neuropsychiatric disorders, collectively known as Timothy syndrome. In 2015, a variant in CACNA1C (p.R518C) was reported to cause cardiac-only Timothy syndrome, a genetic disorder with a mixed phenotype of congenital heart disease, hypertrophic cardiomyopathy (HCM), and LQTS that lacked extra-cardiac features. We have identified a family harboring the p.R518C pathogenic variant with a wider spectrum of clinical manifestations. METHODS: A four-generation family harboring the p.R518C pathogenic variant was reviewed in detail. The proband and his paternal great-uncle underwent comprehensive cardiac gene panel testing, and his remaining family members underwent cascade testing for the p.R518C pathogenic variant. RESULTS: In addition to displaying cardinal features of CACNA1C disorders including LQTS, congenital heart disease, HCM, and sudden cardiac death, family members manifested atrial fibrillation and sick sinus syndrome. CONCLUSION: Our report expands the cardiac phenotype of CACNA1C variants and reflects the variable expressivity of mutations in the L-type Ca2+ channel.
