Rett syndrome genetics — MRCPsych Paper A MCQ

Correct answer: B — De novo X-linked dominant MECP2 pathogenic variant

This is the characteristic developmental trajectory of Rett syndrome: apparently normal early development followed by regression, loss of purposeful hand use, hand stereotypies and slowing of head growth. Classic Rett syndrome is usually caused by a de novo pathogenic variant in MECP2 on the X chromosome and is conventionally classified as X-linked dominant; it predominantly affects girls. Mitochondrial tRNA disorders more often show maternal inheritance and multisystem disease. Imprinting defects cause disorders such as Angelman or Prader–Willi syndrome rather than this specific pattern. Autosomal recessive enzyme deficiencies commonly produce metabolic or systemic features, while autosomal dominant CAG expansions typically cause later-onset disorders with anticipation, such as Huntington disease.

Reference: NHS. Rett syndrome, section ‘What causes Rett syndrome’, last reviewed 17 March 2023. https://www.nhs.uk/conditions/rett-syndrome/