Fragile X Syndrome Premutation Screening

Clinical Background

Fragile X syndrome is the most common inherited disease of mental retardation. The syndrome occurs in approximately 1 in 3,600 males and 1 in 4,000–6,000 females. Around 1 in 250 females carry the premutation.

Women with a family history of fragile X-related disorders, unexplained mental retardation or developmental delay, autism, or premature ovarian insufficiency are candidates for genetic counseling and fragile X premutation carrier screening.

 

Pathogenesis

Fragile X syndrome is transmitted as an X-linked disorder that caused by expansion of a repeated trinucleotide segment of DNA, CGG of the fragile X mental retardation 1 (FMR1) gene.

The number of CGG repeats varies among individuals and has been classified into four groups depending on the repeat size.

Number of (CGG) Repeats

Genotype

Phenotype

< 45

Normal

Unaffected

45-54

Intermediate

Unaffected

55-200

Premutation

Unaffected

Carrier for Fragile X syndrome

>200

Full mutation

Fragile X syndrome

A person with 55–200 repeats usually is phenotypically normal and is said to have a premutation. When more than 200 repeats are present, an individual has a full mutation that results in the full expression of fragile X syndrome in males and variable expression in females secondary to X chromosome inactivation.

 

Important for gene screening

Genetic analysis is the preferred method of diagnosis for fragile X syndrome. Prenatal testing for fragile X syndrome should be offered to known carriers of the fragile X premutation or full mutation.