Parental age effects and Rett syndrome

Am J Med Genet A. 2024 Feb;194(2):160-173. doi: 10.1002/ajmg.a.63396. Epub 2023 Sep 28.


Rett syndrome (RTT) is a progressive neurodevelopmental disorder, and pathogenic Methyl-CpG-binding Protein 2 (MECP2) variants are identified in >95% of individuals with typical RTT. Most of RTT-causing variants in MECP2 are de novo and usually on the paternally inherited X chromosome. While paternal age has been reported to be associated with increased risk of genetic disorders, it is unknown whether parental age contributes to the risk of the development of RTT. Clinical data including parental age, RTT diagnostic status, and clinical severity are collected from 1226 participants with RTT and confirmed MECP2 variants. Statistical analyses are performed using Student t-test, single factor analysis of variance (ANOVA), and multi-factor regression. No significant difference is observed in parental ages of RTT probands compared to that of the general population. A small increase in parental ages is observed in participants with missense variants compared to those with nonsense variants. When we evaluate the association between clinical severity and parental ages by multiple regression analysis, there is no clear association between clinical severity and parental ages. Advanced parental ages do not appear to be a risk factor for RTT, and do not contribute to the clinical severity in individuals with RTT.

Keywords: MECP2; RETT syndrome; clinical severity; parental age; risk factor.

MeSH terms

  • Chromosomes, Human, X
  • Humans
  • Methyl-CpG-Binding Protein 2 / genetics
  • Mutation
  • Parents
  • Rett Syndrome* / diagnosis
  • Rett Syndrome* / epidemiology
  • Rett Syndrome* / genetics


  • Methyl-CpG-Binding Protein 2