Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant
| Autor: | Tomás Ripoll-Vera, Lorenzo Monserrat Iglesias, Raquel Bilbao Quesada, Joel Salazar-Mendiguchía García, Xusto Fernández, Juan Pablo Ochoa, Alfredo Repáraz Andrade, José M. Larrañaga-Moreira, Alba Guitián González, María Alejandra Restrepo Córdoba, Ana Berta Sousa, Luis de la Higuera Romero, Raúl Franco Gutiérrez, Diego A. García, Dulce Brito, Pablo García Pavía, María Luisa Peña-Peña, Julián Palomino-Doza, Soledad García Hernández, Carmen Benito López, Álvaro Rubio Alcaide, M.J. Loureiro, Arsonval Lamounier Junior, Ivonne Johana Cárdenas Reyes, Roberto Barriales-Villa, María Victoria Mogollón Jiménez, Olga Azevedo, Luis R. Lopes, Germán Fernández Ferro, Marcos Cicerchia, Alejandro Rodríguez Vilela, M N Brogger, Inês Cruz, Martín Ortiz |
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| Rok vydání: | 2020 |
| Předmět: |
Proband
Male medicine.medical_specialty Cosegregation Pedigree chart TPM1 Tropomyosin 030204 cardiovascular system & hematology Sudden death 03 medical and health sciences 0302 clinical medicine Internal medicine Medicine Humans Genetic Association Studies Aged Portugal business.industry Hypertrophic cardiomyopathy General Medicine Cardiomyopathy Hypertrophic Middle Aged medicine.disease Penetrance Pedigree Phenotype Spain Mutation Female business Founder effect |
| Zdroj: | Revista espanola de cardiologia (English ed.). 75(3) |
| ISSN: | 1885-5857 |
| Popis: | Introduction and objectives TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. Methods TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. Results The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P .0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ± 7.65 mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. Conclusions TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis. |
| Databáze: | OpenAIRE |
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