What is a genetic disorder?

A genetic disorder results from a pathogenic variant or mutation in an individual’s genetic information, also known as DNA. DNA contains genes, which provide the instructions for making proteins that drive the body’s growth and development. This DNA is stored in the body in structures called chromosomes.

Individuals typically have 23 pairs of chromosomes, with one chromosome from each pair coming from the mother and one from the father. All but one of these chromosomes are the same in males and females. In the 23rd pair of chromosomes, males have an X and a Y chromosome while females have two X chromosomes.

Rett syndrome is caused by a pathogenic variant in the MECP2 gene located in the X chromosome.

The MECP2 Gene

Every cell in our body has the MECP2 gene which provides instructions to make the MeCP2 protein. MeCP2 stands for methyl-CpG binding protein 2. It plays a crucial role in regulating other genes essential for brain cell function, building connections between neuronal cells during brain development, and maintaining these connections throughout life.

Pathogenic variants in the MECP2 gene result in the MeCP2 protein being absent or non-functional. Though Rett syndrome affects multiple organ systems, the most significant impact is seen on brain development, impacting how brain cells communicate and grow. Nearly all individuals with Rett syndrome have one of >300 distinct loss-of-function mutations in the gene.1

Types of Genetic Mutations

Explore some of the common variants associated with Rett syndrome. In these examples, a normal MECP2 gene is represented by the sentence “The dog ran and hid.”

Missense Mutation

“The dog ran and hid.”

“The dog ran and had.”

When a single letter in the DNA changes, resulting in the replacement of the original amino acid with a different one. The severity will depend on the extent to which new amino acid affects protein function.

“The dog ran and hid.”

“The dog ran and end.”

When a single letter in DNA changes and changes the original amino acid to a stop signal, thereby cutting short the protein.

“The dog ran and hid.”

“The dog bra nan dhi d.”

When an extra letter is inserted in the DNA sequence in a number that is not a multiple of 3, thereby causing the amino acids following the insertion(s) to become “out of frame”.

“The dog ran and hid.”

“The dog []ana ndh id.”

When a letter is deleted in the DNA sequence in a number that is not a multiple of 3, thereby causing the amino acids following the insertion(s) to become “out of frame”.

“The dog ran and hid.”

“The dog ran and hid.”

Several letters of the DNA sequence are missing.

MECP2 ON

“The dog ran and hid.”
“The dog bra nan dhi d.”
“The dog ran and hid.”
“The dog ran and hid.”
“The dog [ ]ana ndh id.”

MECP2 OFF

“The dog ran and had.”
“The dog ran and hid.”
“The dog ran and hid.”
“The dog ran and had.”
“The dog ran and hid.”

Some cells use the X-chromosome that carries the correct copy of the DNA sequence, while others use the X-chromosome that carries the incorrect copy (incorrect copy resulting from any of the above-mentioned reasons). The proportion of cells that use one or the other copy varies due to random inactivation of one of the X-chromosomes.

MECP2 X-Inactivation

Since females have two copies of the X chromosome in every cell, one of these copies gets randomly “turned off” or inactivated during embryonic development. This process is called X-inactivation and ensures equal gene expression and production of protein between males who only have one X chromosome and females.

In Rett syndrome, this inactivation means that the X chromosome that remains “on” may or may not have the MECP2 variant. Skewed X-inactivation, when one X chromosome is inactivated more often than the other, may impact the severity of symptoms in Rett syndrome, meaning more MECP2 variant means more severe symptoms. The degree of the inactivation of the X chromosome with the variant, as well as the position of the variant along the MECP2 gene sequence and type of variant, may influence the course and severity of Rett syndrome.

Rett Syndrome in Males

Although rarer than in females, Rett syndrome can occur in males and often with more severe features. Because males have only one X chromosome, a mutation in their single MECP2 gene affects all cells, unlike females, who experience random X-inactivation.

Inheritance

Pathogenic variants in the MECP2 gene are currently believed to be de novo in 99% of cases. That means that the variant is new or spontaneous, not known to be inherited from a parent except in incredibly rare cases. Additionally, having another child with Rett syndrome is incredibly rare, the risk estimated to be <1%.2

Genetic Testing

Several types of genetic tests may be able to reveal a pathogenic variant in the MECP2 gene: genome sequencing, exome sequencing, gene panel testing, single gene testing, MLPA, and microarray. It is important that the testing ordered can identify all types of pathogenic variants in the MECP2 gene, as not all types of testing will be able to detect both spelling errors (sequencing changes) and deletions.

A small percentage of individuals may not have an identifiable pathogenic variant in the MECP2 gene but may still have a clinical diagnosis of Rett syndrome. Alternatively, some individuals may have a pathogenic variant in the MECP2 gene but not have received a clinical diagnosis of Rett syndrome. These individuals may receive a clinical diagnosis of classic or atypical Rett syndrome in the future, or they may receive a clinical diagnosis of MECP2-related disorder.

Our Collaborators

Thank you to our collaborators for helping IRSF develop this content:

Sophia Viola, MPH
  1. Cary Fu, Dallas Armstrong, Eric Marsh, David Lieberman, Kathleen Motil, Rochelle Witt, Shannon Standridge, Paige Nues, Jane Lane, Tristen Dinkel, Monica Coenraads, Jana von Hehn, Mary Jones, Katie Hale, Bernhard Suter, Daniel Glaze, Jeffrey Neul, Alan Percy, Timothy Benke – Consensus guidelines on managing Rett syndrome across the lifespan: BMJ Paediatrics Open 2020;4:e000717.

  2. https://www.ninds.nih.gov/health-information/disorders/rett-syndrome