Is Rett syndrome inherited from parents?

[Anonymous]

Is Rett syndrome inherited from parents?

[Genetic Counselor]

Rett syndrome is a genetic disorder, but in most cases, it is not inherited from either parent. More than 99% of affected individuals are the only known person with the condition in their family. This usually happens because a new genetic change, known as a de novo variant, occurs during the formation of an egg or sperm or during early embryonic development. NCBI

What does de novo mean?
A de novo variant is a genetic change that occurs for the first time in an individual rather than being passed down through a family.
For example, a child may be born to two healthy parents with no family history of neurological disorders. During the formation of the reproductive cells or shortly after fertilization, a pathogenic variant may arise in the MECP2 gene. The child may subsequently develop Rett syndrome.
In such cases, the parents may not carry the variant in their blood or other routinely tested tissues.
Therefore, having no family history does not exclude a genetic disorder. Many genetic conditions arise spontaneously.

Can Rett syndrome be inherited from the mother?
Yes, although this is uncommon.
Rett syndrome associated with MECP2 follows an X-linked dominant inheritance pattern. The MECP2 gene is located on the X chromosome, one of the two sex chromosomes.
Typically, females have two X chromosomes, whereas males have one X and one Y chromosome.
A female who carries a pathogenic MECP2 variant may have Rett syndrome or may have mild or no obvious symptoms. The severity can vary because of a biological process called X-chromosome inactivation.
During early development, one of the two X chromosomes is largely inactivated in each cell of a female. If the X chromosome carrying the pathogenic variant is predominantly inactivated in relevant tissues, the mother may have few or no clinical symptoms.
If a mother is confirmed to carry a heterozygous pathogenic MECP2 variant, each pregnancy has a 50% chance of inheriting that variant, regardless of the child’s sex. However, the clinical outcome can differ between male and female offspring.

What is germline mosaicism?
Germline mosaicism is another important concept in genetic counselling.
It occurs when a genetic variant is present in some of a parent’s reproductive cells, such as eggs or sperm, but is absent from the parent’s blood cells or other tested tissues.
For example, both parents may have negative blood tests for the child’s MECP2 variant. However, one parent may have the variant in a proportion of their reproductive cells.
This explains why a condition can occasionally recur in a family even when neither parent appears to carry the variant.
Consequently, a negative parental blood test does not completely eliminate the possibility of recurrence.

What is the recurrence risk for future pregnancies?
When the variant is confirmed to be de novo and is not detected in either parent’s blood, the recurrence risk is generally low, often estimated at less than 1%. However, it is not zero because germline mosaicism may be present.
If a mother carries a heterozygous pathogenic variant, the risk of transmitting it is 50% in each pregnancy.
Genetic counselling can help families understand their individual risk. Depending on the circumstances, options may include targeted parental testing, prenatal diagnosis through chorionic villus sampling (CVS) or amniocentesis, and preimplantation genetic testing.

[Author]

Posts