<Algunas mutaciones que contribuyen en el autismo y surgen de forma espontánea, puede ser confundida con mutaciones hereditarias.
Varios estudios pueden haber pasado por alto esta clase de mutaciones del “mosaico”. Los investigadores presentaron un trabajo inédito en la conferencia de la Sociedad Americana de Genética Humana de 2018 en San Diego California.
Las mutaciones espontaneas o de novo, surgen en uno de los progenitores y afecta cierta proporción de las células progenitoras: Si la mutación es solo una célula o una pequeña fracción de células, será indetectable en la sangre del progenitor, pero si la proporción es grande, la mutación debería aparecer allí.
La presencia de una mutación en el esperma o células del ovulo, permite que se transmita al niño. Pero estas mutaciones son definidas como “de novo”, es decir que no son heredadas, porque no estuvieron presentes en las generaciones anteriores.
Queremos saber si una mutación es un mosaico en los padres,” dice Hákon Jónsson, un investigador de deCODE genetics, la cual es una compañía en Reikiavik, Islandia, quien presento los hallazgos “Si ignoras este procedimiento, omites la mitad de las mutaciones de novo que se comparten entre hermanos”
Los hallazgos deberían ser una alerta de precaución para los investigadores, dice Jonathan Sebat, jefe de Center for Molecular Genomics of Neuropsychiatric Diseases en la Universidad de California, San Diego, quien no participo en el estudio.
“La mayoría de los genetistas están particularmente enfocados en las
[mutaciones clásicas de novo]
, por lo que dejan escapar esos puntos clave”. “Si hay una pérdida de función heredada, que de hecho es un mosaico en el padre, lo están desperdiciando y estos tienen riesgos de recurrencia.”.
Hermanos compartiendo
Jónsson y sus colegas observaron los genes en 1.007 pares de hermanos de 251 familias. Primero, identificaron en cada niño sus cromosomas paternos y maternos. Buscaron a dos hermanos que compartieran un cromosoma de uno de sus progenitores y lleven la misma mutación en ella. También buscaron casos, en los cuales, dos hermanos comparten una mutación y un tercero no. Luego, observaron la sangre de los padres para verificar la mutación.
Encontraron 878 de estas mutaciones. Si la mutación no es detectable en la sangre de los padres, los investigadores concluyen que afecta solo a una pequeña proporción de sus células. Sin embargo, en más de la mitad de los casos, los investigadores encontraron la mutación en la sangre de los padres.
La presencia de una mutación en la sangre de los padres, podría llevar a otros a concluir erróneamente que, se heredó de una generación anterior. Los investigadores estiman que el 4 por ciento de las mutaciones, que se cree que son heredadas, pueden ser de hecho, mutaciones de mosaico de novo.
Clasificar de manera precisa estas mutaciones como “de novo” podría haber reforzado el caso de ciertos genes que contribuyen al autismo o proporcionado información valiosa para una familia, dice Anne Goriely, catedrática de genética humana en la Universidad de Oxford, Reino Unido, quien no participo en el estudio.
Sin embargo, para obtener estos resultados requirió acceso a familias numerosas, de las 251 familias, 13 tienen 8 hijos o más. “La mayoría de las personas tiene familias pequeñas y no hay genealogía,” Dice Gloriely. “La mayoría de estudios no tiene facultad de hacer esto.”
Calculadora de Riesgos:
Los investigadores también analizaron el riesgo de que una mutación mosaico de novo pueda ser transmitida a más de un niño. Observaron las mutaciones de novo compartidas por hermanos en dos familias, una con 17 hijos y la otra con 10. Los investigadores encontraron que, los hermanos son más propensos a compartir una mutación de novo, si está presente en gran proporción de las células sanguíneas de los padres.
Las probabilidades de que, una mutación de novo provenga de un padre mosaico, disminuyen con la edad de los mismos. Además, las madres tienen más probabilidad de transmitir mutaciones mosaicas, mientras que los padres son más propensos a tener mutaciones en el esperma que podrían dar lugar a una clásica mutación de novo.
Basándose en estos hallazgos, el equipo desarrolló una calculadora para determinar el riesgo de recurrencia de una mutación dada. Usaron esta herramienta, en una familia con dos hijos, que tienen una mutación de novo que conduce a la epilepsia. Encontraron que, el riesgo de que otro niño de esta familia tenga esta mutación, es 83 veces mayor que para una mutación clásica de novo.
Desde otro punto de vista, en la conferencia, los investigadores mostraron el contrapunto: Las mutaciones que parecen ser espontaneas en un niño, podría de hecho ser mosaicas en el padre. Los investigadores fueron capaces de detectar una mutación de novo relacionada al autismo en el esperma de un padre, en 4 de 20 familias que estudiaron.
En una familia, en ese estudio, tres niños tienen una mutación de gen de riesgo de autismo GRIN2B, aunque, solo uno de los hermanos tenia diagnóstico de autismo, dice Martin Breuss, becario postdoctoral en el laboratorio Joseph Gleeson de la Universidad de California, San Diego, quien presento los hallazgos. Una vez que la mutación fue descubierta se logró observar con más detenimiento y se encontró que todos los hermanos tienen rasgos de autismo.
NOTA DEL EDITOR:
Los hallazgos discutidos en el artículo fueron publicados en la edición de diciembre de 2018 de Nature Genetics 1. El artículo apareció originalmente en Spectrum el 19 de octubre de 2018, según los datos presentados en la conferencia de la Sociedad Americana de Genética Humana de 2018 en San Diego, California.
Spectrum ofrece noticias y
análisis de los avances en la investigación del autismo. Los
fondos para Spectrum provienen de la Simons Foundation Autism
Research Initiative (SFARI), pero el medio de
comunicación es editorialmente independiente .
©Fundación Simons, Spectrum y autores, todos los derechos reservados.
©Traducción Pamela Palomeque
Este artículo no puede ser reproducido ni copiado sin autorización expresa.
Bibliografía:
1. Jónsson H, Sulem P, Arnadottir G, et al. Multiple transmissions of de novo mutations in families. Nat Genet. 2018;50(12):1674-1680. [PubMed]
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