Fragile X Syndrome

Fragile X syndrome is the most common cause of inherited intellectual disability. It can occur in any ethnic group and affects approximately 1 in 3,600 males and 1 in 4,000 – 6,000 females. Intellectual disability may range from learning disabilities to severe mental retardation and autism. Behavioral traits may include hyperactivity, poor eye contact, and speech disturbances. Symptoms are usually more severe in males than in females, and adult males may exhibit pronounced physical characteristics including enlarged ears and a long face with a prominent chin.

Our Test
At GenPath we offer Fragile X testing as an individual test or as a component of InheriGen Plus. We employ the most highly recommended methodology for Fragile X carrier testing, as recently highlighted in Genetics In Medicine:

Methylation polymerase chain reaction enabled high throughput, high resolution, and semiquantitative methylation assessments of FMR1 alleles, as well as determinations of CGG repeat length. Results for all samples were concordant with corresponding Southern blot analyses. As a result, this study presents a polymerase chain reaction-based method for comprehensive FMR1 analysis. In addition, the identification of novel methylation mosaic patterns revealed after polymerase chain reaction and capillary electrophoresis may be relevant to several FMR1 disorders.
J Mol Diagn. 2010 Sep;12(5):589-600. Epub 2010 Jul 8.
An information-rich CGG repeat primed PCR that detects the full range of fragile X expanded alleles and minimizes the need for southern blot analysis.
Chen L, Hadd A, Sah S, Filipovic-Sadic S, Krosting J, Sekinger E, Pan R, Hagerman PJ, Stenzel TT, Tassone F, Latham GJ.
Source: Department of Diagnostic Research and Technology Development, Asuragen, Inc., Austin, Texas 78744, USA

 

Interpretive Information
Expansions in the full mutation range are associated with hypermethylation of the FMR1 gene and loss of gene activity.
Interpretation is based on the number of trinucleotide CGG repeats:

<45 repeats = Normal
45-54 repeats = Intermediate
55-200 = Premutation
>200 = Full Mutation

Who Should Be Offered Carrier Testing?
According to ACOG Committee opinion Number 469, carrier testing for Fragile X may be offered for women with a family history of
fragile X-related disorders
unexplained mental retardation or developmental delay
autism
premature ovarian insufficiency (or elevated FSH <40 yrs)

Women who request fragile X carrier screening, regardless of family history, should be offered FMR1 DNA mutation analysis after genetic counseling about the risks, benefits, and limitations of screening.

How is Fragile X Syndrome Inherited?
Fragile X syndrome is inherited in an X-linked manner, because the fragile X gene (FMR1) is on the X chromosome. Females who have between 55-199 CGG repeats in the FMR1 gene are premutation carriers for fragile X syndrome. When a female premutation carrier for fragile X syndrome has children, there is a 50% chance that she will pass her X chromosome with a normal CGG repeat, and a 50% chance she will pass the X chromosome with the premutation. If she passesthe X chromosome with the premutation to a child, it may remain stable, or it may expand, possibly to a full mutation. In general, the higher the mother’s CGG repeat number, the greater the chance for it to expand to a full mutation in the next generation.

When a male is a premutation carrier for fragile X syndrome, it usually does not expand to a full mutation when passed on to his daughters. A male carrier never passes on the fragile X gene to his sons, as he passes on his Y chromosome to his son.

A woman with a full mutation has a 50% chance of passing it to her baby in each pregnancy. Men with a full mutation generally do not reproduce.

Some individuals have a CGG repeat size between 45-54, which is considered the grey zone. While a repeat size in the grey zone has the potential to expand to the premutation range if passed to a child, a repeat size in the grey zone is not expected to expand to a full mutation in one generation.