Monogenic disorders that mimic the phenotype of Rett syndrome

Neurogenetics. 2018 Jan;19(1):41-47. doi: 10.1007/s10048-017-0535-3. Epub 2018 Jan 10.


Rett syndrome (RTT) is caused by mutations in methyl-CpG-binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. We performed a retrospective chart review on n = 319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup. From this group, we characterized those who (1) possessed features that were compatible with RTT based on clinical judgment, (2) subsequently underwent MECP2 sequencing and/or MECP2 deletion/duplication analysis with negative results, and (3) ultimately arrived at a diagnosis other than RTT with WES. n = 7 patients had clinical features overlapping RTT with negative MECP2 analysis but positive WES providing a diagnosis. These seven patients collectively possessed pathogenic variants in six different genes: two in KCNB1 and one each in FOXG1, IQSEC2, MEIS2, TCF4, and WDR45. n = 2 (both with KCNB1 variants) fulfilled criteria for atypical RTT. RTT-associated features included the following: loss of hand or language skills (n = 3; IQSEC2, KCNB1 x 2); disrupted sleep (n = 4; KNCB1, MEIS2, TCF4, WDR45); stereotyped hand movements (n = 5; FOXG1, KNCB1 x 2, MEIS2, TCF4); bruxism (n = 3; KCNB1 x 2; TCF4); and hypotonia (n = 7). Clinically based diagnoses can be misleading, evident by the increasing number of genetic conditions associated with features of RTT with negative MECP2 mutations.

Keywords: Mendelian disorders; Mimics; Rett syndrome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carrier Proteins / genetics
  • Exome Sequencing
  • Female
  • Forkhead Transcription Factors / genetics
  • Gene Deletion
  • Gene Duplication
  • Guanine Nucleotide Exchange Factors / genetics
  • Homeodomain Proteins / genetics
  • Humans
  • Male
  • Methyl-CpG-Binding Protein 2 / genetics
  • Molecular Diagnostic Techniques
  • Nerve Tissue Proteins / genetics
  • Phenotype
  • Retrospective Studies
  • Rett Syndrome / diagnosis*
  • Rett Syndrome / genetics*
  • Shab Potassium Channels / genetics
  • Transcription Factor 4 / genetics
  • Transcription Factors / genetics


  • Carrier Proteins
  • FOXG1 protein, human
  • Forkhead Transcription Factors
  • Guanine Nucleotide Exchange Factors
  • Homeodomain Proteins
  • IQSEC2 protein, human
  • KCNB1 protein, human
  • MECP2 protein, human
  • MEIS2 protein, human
  • Methyl-CpG-Binding Protein 2
  • Nerve Tissue Proteins
  • Shab Potassium Channels
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • WDR45 protein, human