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When you or someone in your family are told you are a “carrier” for a Fragile X mutation, many questions arise. Do you have a premutation or full mutation? What does it mean for your health, your family and your future? Does the size of your FMR1 gene matter?
A carrier has an altered form of a gene that can lead to having a child or grandchild with a genetic disorder. We are all carriers of gene mutations, many of which are “silent.” This means we can pass the gene on but suffer no ill effects from it ourselves. It is only through genetic testing that we know which ones we carry. Some genes are on the non-sex chromosomes (numbered 1-22), which are the same in males and females, and some are on the sex chromosomes, which are the X and Y chromosomes.
Traditionally, a carrier of a genetic mutation is defined as a person who inherits an altered form of a gene but shows no effects of that mutation. However, in Fragile X this definition does not exactly fit, as carriers of a premutation are at risk to develop Fragile X-associated Disorders including fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI).
The gene for Fragile X (the FMR1 gene) is on the X chromosome, which is why fragile X syndrome is called an X-linked disorder. Often in these disorders, only females are carriers and only males are affected. However, in Fragile X, both males and females can be carriers, and both can be affected by the condition. This occurs because the changes in the FMR1 gene go through stages as it is passed down in a family. These stages start with the normal gene and then proceed to the premutation and then the full mutation. The differences in the stages are determined by the number of “CGG repeats” (repeats of a DNA pattern). In most other X-linked conditions, there is no middle “premutation” state, so males with the mutation are either affected or non-carriers.
A premutation carrier is an individual, male or female, who has between 55-200 CGG repeats in the Fragile X (FMR1) gene. The full mutation is defined as over 200 CGG repeats. Occasionally a female with a full mutation shows little or no effect of the full mutation and is sometimes referred to as “full mutation carrier.” However, most of the time, the term “carrier” is used for those with a premutation.
An allele is a term to describe one’s gene, like green apples are a specific form of an apple. Some individuals have what is called an “intermediate” or “grey area” sized allele. These are alleles with 45-54 CGG repeats. They are not considered to be mutations and do not appear to be associated with any clinical or medical issues, developmental disabilities or social/emotional difficulties. These alleles are identified as such because there is a small chance that they are mildly unstable and may expand to a premutation in future generations. There is no reported risk for an individual with an intermediate sized allele to have a child with a full mutation. Generally, we don’t use the term “carrier” for those with an intermediate allele.
Females with a premutation are at risk to have a child, male or female, with fragile X syndrome. The magnitude of this risk is related to the number of CGG repeats identified in her FMR1 gene. The larger the number, the higher the risk for expansion from a permutation to a full mutation if it is passed on.
Among the first effects reported in premutation carriers were an increased rate of twin births and of premature ovarian failure (POI)... We now know that approximately 20-25% of women with a premutation experience FXPOI, which is characterized by infertility, decreased ovarian function, early menopause or irregular cycles. Women with the full mutation do not experience FXPOI or increased twinning rates. FXTAS is another medical effect of the premutation. It is more common in male carriers, but has been reported in about 5-8 percent of female carriers over the age of 50.
Given the stresses and emotional aspects of parenting a child with disabilities, along with stresses that can accompany the various reproductive issues associated with having a premutation (risks for an affected child, fertility and prenatal issues), researchers find it difficult to establish emotional effects which are a direct biological result of the premutation. Though most women with a premutation show no significant mental health issues, some have reported increased general anxiety, shyness and social anxiety. In addition, there is evidence that women with the premutation are at increased risk for depression. It is therefore recommended that any premutation carrier who is concerned about depression seek the services of a mental health professional.
Male can also carry the Fragile X premutation. A male carrier will pass his premutation (as a premutation, not a full mutation) on to all of his daughters and none of his sons. There is no reported risk for a male premutation carrier to have a daughter with fragile X syndrome. However, there is a risk for fragile X syndrome in his grandchildren through his daughters.
The most significant issue for males with a premutation is the risk for FXTAS.
Other than the FXTAS risk in older males, the vast majority of males with the premutation are clinically unaffected. There have been reports of a small subset of boys with a premutation who have an additional diagnosis of autism, ADHD, or other learning/behavioral disorders. It is possible that in a small subset of boys, these developmental disorders may be caused by an interaction of various genetic and non-genetic factors, one of which may be the FMR1 premutation. Research regarding this possible association is ongoing.