Mosaic Mutations May Hold Key to Understanding Rett’s Development

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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Mosaic mutations

Genetic screening for mosaic mutations — those present in only some cells in the body — may be useful to understand disease development and severity in patients with Rett syndrome and other rare genetic disorders, a case report study says.

The study, “De novo mosaic MECP2 mutation in a female with Rett syndrome,” was published in Clinical Case Reports.

Rett syndrome is a rare genetic disorder characterized by developmental and intellectual disabilities. It mostly affects girls. Rett patients typically have severe learning, communication and motor coordination impairments. The condition is caused by mutations in the MECP2 gene — located on the X chromosome — that provides instructions to make a protein called MeCP2. This protein is responsible for maintaining synapses — the junctions between two nerve cells that allow them to communicate.

Now, for the first time, a group of researchers from The Cyprus Institute of Neurology described the clinical case of a young girl who carried a rare mosaic de novo nonsense mutation in the MECP2 gene and showed classical symptoms of Rett syndrome. De novo mutations are mutations that appear for the first time in a individual, instead of being inherited from the parents; nonsense mutations are single nucleotide mutations that make proteins shorter and may result in malfunction of the protein; nucleotides are the building blocks of DNA.

At the time of referral the girl, 5, showed classical signs of Rett syndrome, including autistic features, severe motor and cognitive impairments, and speech difficulties. Her parents were unaffected by the disorder. Nevertheless, the patient was referred for investigation of Prader-Willi syndrome and Angelman syndrome. The girl’s DNA was isolated from blood samples.

Genetic analysis found no signs of Prader-Willi or Angelman syndrome. But the screening identified a de novo mosaic mutation in the third exon (the coding sequence of a gene that provides instructions to make proteins) of the MECP2 gene.

Biochemical analysis confirmed that both parents carried a normal MECP2 gene. Next-generation sequencing (NGS) found that approximately 25% of the cells in the girl’s body contained the MECP2 mutation. NGS is a type of genetic sequencing that reads millions of small fragments of DNA in parallel.

“[D]espite the relatively low level of mosaicism (~25%), the patient is exhibiting the full spectrum of Rett syndrome [symptoms … which may be explained by the fact that] truncating mutations within MECP2 have been associated with a more severe manifestation, as compared to missense mutations which may cause a milder or atypical [Rett syndrome],” researchers said. Truncating mutations are those that lead to the production of a an incomplete and usually nonfunctional protein; missense mutations are single-nucleotide mutations that alter protein composition.

“The introduction of next-generation sequencing (NGS) into routine genetic diagnosis is expected to play a key role in the future investigation of mosaicism in general. The detection and thorough investigation for somatic mosaicism in RS patients as well as in other syndromes is a valuable tool for uncovering unknown mechanisms of disease development and severity assessment based on tissue specificity,” scientists concluded.