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Decodificación de la complejidad del empalme: el análisis genómico integrado revela dos nuevas variantes patógenas en
Yingwen Liu1,2,3, Lulu Yan1,2,3, Yuxin Zhang1,2,3
1The Central Laboratory of Birth Defects Prevention and Control, The Affiliated Women and Children's Hospital of Ningbo University, Ningbo, 315000, Zhejiang, China.
Genes & genomics
|September 1, 2025
Resumen
Este estudio identifica dos nuevas variantes del sitio de empalme del gen DMD en pacientes con distrofinopatía, ampliando el espectro de diagnóstico genético para esta enfermedad muscular vinculada al X. Los patrones de inactivación del cromosoma X pueden explicar las mujeres portadoras asintomáticas.
Área de la Ciencia:
- La genética
- Biología molecular
- Neurología
Sus antecedentes:
- La distrofinopatía es un trastorno muscular recesivo ligado al X grave causado por mutaciones en el gen DMD.
- Las variantes intrónicas profundas en el gen DMD se reconocen cada vez más, lo que requiere comprender sus mecanismos patógenos para mejorar el diagnóstico y el tratamiento.
Objetivo del estudio:
- Identificar y caracterizar dos nuevas variantes del sitio de empalme en el gen DMD en familias afectadas por la distrofinopatía.
- Investigar el impacto funcional de estas variantes en el empalme de genes DMD y la producción de proteínas.
Principales métodos:
- Se realizó la secuenciación completa del exoma en dos pacientes pediátricos diagnosticados con distrofia muscular de Duchenne (DMD).
- Las nuevas variantes de empalme fueron confirmadas por la secuenciación de Sanger en miembros de la familia.
- Se utilizaron ensayos de minigene para evaluar los efectos de empalme de las variantes identificadas.
- Se realizó un análisis de inactivación del cromosoma X (XCI) para las mujeres portadoras.
Principales resultados:
- Se identificaron dos nuevas variantes intrónicas en el gen DMD: c.9807+2dup y c.5739+326T>G.
- Estas variantes llevaron a un empalme alterado, lo que resultó en la producción de proteínas de distrofina truncadas.
- El análisis de XCI reveló patrones sesgados en una madre portadora, lo que potencialmente explica su estado asintomático.
Conclusiones:
- El estudio identificó dos nuevas mutaciones de empalme de DMD, ampliando el espectro conocido de variantes de DMD.
- Se proporcionó un diagnóstico genético preciso para la distrofinopatía, lo que permitió intervenciones terapéuticas oportunas.
- Los patrones de inactivación del cromosoma X pueden aclarar la presentación clínica de las mujeres portadoras de DMD.
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