RESUMEN
Introducción y objetivos: TPM1 es uno de los principales genes en la miocardiopatía hipertrófica (MCH). La información clínica sobre portadores es relativamente escasa, lo cual limita la interpretación de los estudios genéticos. Nuestro objetivo es establecer la correlación genotipo-fenotipo de la variante p.Arg21Leu de TPM1 en una serie de familias. Métodos: Se evaluó el TPM1 mediante secuenciación de nueva generación en 10.561 probandos con cardiopatías hereditarias. Se genotipificó a los familiares mediante Sanger. Se analizaron la cosegregación, las características clínicas y los eventos cardiovasculares. Se estimó la distribuición geográfica de las familias en Portugal y España. Resultados: Se identificó la variente p.Arg21Leu de TPM1 en 25/4.099 (0,61%) casos con MCH y estaba ausente en 6.462 controles con otras cardiopatías familiares (p<0,0001). Se identificó a 83 portadores (31 probandos). La LOD score combinada para cosegregación fue 3,95. La probabilidad acumulada de diagnóstico en portadores a los 50 años fue del 50% para los varones y el 25% para las mujeres. El 17 de los varones y el 46% de las mujeres no estaban afectadas a los 70 años. El grosor medio del ventrículo izquierdo fue 21,4 ±7,65mm. El riesgo de muerte súbita-MCH fue bajo en 34 (77,5%), intermedio en 8 (18%) y alto en 2 (4,5%) de los portadores. La supervivencia libre de eventos cardiovasculares fue del 87,5% a los 50 años. El 6% de los portadores eran homocigotos y el 18% tenían una variante adicional. El origen de las familias se concentró en Galicia, Extremadura y norte de Portugal, lo que indica un efecto fundador. Conclusiones: P.Arg21Leu es una variante patogénica de TPM1 asociada con MCH de penetrancia tardía/incompleta y pronóstico generalmente favorable (AU)
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 ±7.65mm. 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 (AU)
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Cardiomiopatía Hipertrófica/genética , Mutación/genética , Tropomiosina/genética , Estudios de Asociación Genética , Fenotipo , Portugal , EspañaRESUMEN
BACKGROUND: The enigma of Traumatic Brain Injury (TBI), reflected in recent scientific literature, is its uncertain consequences, variability of the final prognosis with apparently similar TBI, necessity for peripheral biomarkers, and more specific predictive models. OBJECTIVES: To study the relationship between serum S100B and survival in TBI patients in various serious situations; the S100B level in patients without traumatic pathology or associated tumour, subjected to stressful situations such as neurological intensive care unit (NICU) stay; the possible overestimation caused by extracerebral liberation in TBI patients and associated polytraumatism; the predictive cutoffs to determine the most sensitive and specific chronology; and achieve a predictive prognostic model. METHODS: Patients admitted to the NICU within 6 hours after TBI were selected. We measured: a) clinical: exitus yes/no; age and gender, traumatic mechanism, polytraumatism yes/no, GCS score, unconsciousness duration, amnesia duration, neurological focality, and surgical interventions; b) radiological: CT scan for radiological lesions; c) biochemical: serum SB100B at 6, 24, 48 and 72 hours after TBI and drug abuse detected in the urine; d) GOS on hospital discharge. RESULTS: N: 149 TBI patients, independent of polytraumatism, mean serum S100B at 6, 24, 48, and 72 hours: 2.1, 1.3, 1.2, and 0.6 microg/L, respectively; N: 124 without associated polytraumatism, S100B at 6, 24, 48, and 72 hours: 2.0, 1.4, 1.3, and 0.6 microg/L; N: 50 control I S100B 24 hours: 0.17 microg/L (0.04 - 0.56) and 25 healthy subjects S100B 0.057 microg/L (0.02-0.094). CONCLUSIONS: Significantly higher S100B levels are observed on exitus, with excellent TBI prognosis and evolution performance. Hospital stay in the NICU produces significant increases in S100B compared to healthy subjects, without invalidating it as a biomarker. Polytraumatism associated to TBI does not significantly alter S100B levels. S100B at 24 hours > or = 0.90 microg/L appears to predict unfavourable TBI evolution with a NPV: 94.2% and PPV: 54.9%. We propose a predictive model when we associate S100B at 24 hours with amnesia duration over 30 minutes with a NPV of 85.5% and a PPV of 83.3%.
