, Volume 19, Issue 1, pp 41–47 | Cite as

Monogenic disorders that mimic the phenotype of Rett syndrome

  • Siddharth Srivastava
  • Sonal Desai
  • Julie Cohen
  • Constance Smith-Hicks
  • Kristin Barañano
  • Ali Fatemi
  • SakkuBai NaiduEmail author
Original Article


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.


Rett syndrome Mendelian disorders Mimics 



We would like to thank the families for their participation.

Funding information

Dr. Srivastava is supported by an NIH grant, 4T32GM007748-38.

Compliance with ethical standards

The Institution Review Board of the Johns Hopkins University School of Medicine approved this study under an IRB exemption protocol (IRB00098913).

Conflicts of interest

JC is a paid consultant for Invitae, and AF is a paid consultant for Ambry Genetics and Aevi Genomic Medicine.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyBoston Children’s HospitalBostonUSA
  2. 2.Hugo W. Moser Research Institute at Kennedy Krieger InstituteBaltimoreUSA
  3. 3.Department of NeurologyThe Johns Hopkins HospitalBaltimoreUSA
  4. 4.Department of PediatricsThe Johns Hopkins HospitalBaltimoreUSA

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