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Los exomas esporádicos del autismo revelan una red de proteínas altamente interconectadas de mutaciones de novo
Brian J O'Roak1, Laura Vives, Santhosh Girirajan
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Nature
|April 13, 2012
Resumen
Las mutaciones de novo, a menudo paternas, están vinculadas al riesgo de trastorno del espectro autista (TEA), especialmente con el aumento de la edad paterna. Las mutaciones disruptivas se dirigen a redes genéticas clave, ofreciendo nuevas vías diagnósticas y terapéuticas para ASD.
Área de la Ciencia:
- Genética La genética.
- Trastornos del desarrollo neurológico Trastornos del desarrollo neurológico
- La medicina genómica es la medicina genómica.
Sus antecedentes:
- Los trastornos del espectro autista (TEA) tienen una base genética significativa, sin embargo, la causa sigue siendo desconocida en más del 70% de los casos.
- Se hipotetiza que las familias esporádicas o simplex, que carecen de una historia previa de TEA, involucran mutaciones de novo.
- Comprender estos fundamentos genéticos es crucial para el diagnóstico y el tratamiento.
Objetivo del estudio:
- Investigar el papel de las mutaciones de novo en los TEA esporádicos.
- Identificar genes y vías específicas implicadas en el desarrollo de TEA.
- Explorar la relación entre la edad paterna y las tasas de mutación de novo en TEA.
Principales métodos:
- Secuenciación del exoma entero de 189 nuevos y 20 trios padre-hijo previamente reportados con TEA esporádico.
- Secuenciación exoma de 50 hermanos no afectados de estas familias.
- Cribado de mutaciones en genes candidatos (CHD8, NTNG1, GRIN2B, LAMC3, SCN1A) en 1.703 sujetos de prueba con TEA.
Principales resultados:
- Las mutaciones puntuales de novo fueron predominantemente paternas (proporción de 4 a 1) y se correlacionaron con la edad paterna.
- El 39% de las mutaciones graves de novo afectaron a una red de remodelación de β-catenina / cromatina asociada con genes candidatos a TEA.
- Se encontraron mutaciones recurrentes en CHD8 y NTNG1; se identificaron mutaciones adicionales de novo en GRIN2B, LAMC3 y SCN1A.
Conclusiones:
- Las mutaciones de novo contribuyen significativamente al riesgo de TEA, particularmente en familias simplex.
- La edad paterna es un factor de riesgo, probablemente debido al aumento de las tasas de mutación de novo.
- Los genes y redes identificados proporcionan objetivos para futuros diagnósticos y terapias de TEA, a pesar de la extrema heterogeneidad del locus.
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