Rett Syndrome Inheritance: MECP2, CDKL5, FOXG1 Genetics and Recurrence Risk

Rett syndrome is a neurodevelopmental disorder almost exclusively affecting females. Recurrence risk depends on the gene and inheritance pattern.

Classic Rett (MECP2, X-linked Dominant)

• De novo mutations: >99% of cases; parents typically unaffected. Recurrence risk <1% (gonadal mosaicism possible).
• Inherited from mother: Rare. Mother may be asymptomatic (favorable X-inactivation) or mildly affected.
• Recurrence if mother is carrier: 50% to each child. Sons: usually severe neonatal encephalopathy (lethal). Daughters: variable severity (X-inactivation skew).

Atypical Rett Variants

• CDKL5 Deficiency Disorder (CDD): X-linked dominant; early-onset epileptic encephalopathy. Mostly de novo; recurrence risk low (<1% mosaicism).
• FOXG1 Syndrome: Autosomal dominant (14q12); congenital variant. Mostly de novo; recurrence risk low.

Genetic Counseling Essentials

• Parental testing for detected variant (blood, saliva).
• If negative → de novo; reassure low recurrence but discuss gonadal mosaicism.
• If positive → 50% risk; prenatal diagnosis (CVS/amnio) or PGD available.
• X-inactivation studies in carrier mothers may predict daughter severity.

Male siblings of affected females should be tested if MECP2 variant found.