The first genetic test to aid in the diagnosis of Fragile X Syndrome

The first genetic test to aid in the diagnosis of Fragile X Syndrome

Last Updated on February 26, 2020 by Joseph Gut – thasso

February 26, 2020 – Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability.The average IQ in males is under 55, while about two thirds of females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech.  Hyperactivity is common, and seizures occur in about 10% of affected individuals. Fragile X syndrome has an X-linked dominant inheritance.  It is typically caused by an expansion of the CGG triplet repeat within the FMR1 (fragile X mental retardation 1) gene on the X chromosome. This results in silencing (methylation) of this part of the gene and a deficiency of the resultant FMR protein, which is required for the normal development of connections between neurons. Diagnosis requires genetic testing to determine the number of CGG repeats in the FMR1gene. Normally, there are between 5 and 40 repeats; fragile X syndrome occurs with more than 200. A premutation is said to be present when the gene has between 40 and 200 repeats; women with a premutation have an increased risk of having an affected child. Testing for premutation carriers may allow for genetic counseling. There is no cure.
The American Food and Drug Administration (FDA) just authorized marketing of the first genetic test to detect the genetic conditions behind the FXS, which in turn is the most common known cause of inherited developmental delay and intellectual disability. The test is intended as an aid in diagnosing FXS and is to be used along with the evaluation of a patient’s family history and clinical signs and symptoms of FXS. Additionally, this test is intended for use in adults who may be carriers of genetic alterations in the FMR1 gene. Particularly in affected children, early diagnosis is key to helping through early intervention.

According to the Centers for Disease Control and Prevention (CDC), approximately 1 in 4,000 males and 1 in 8,000 females in the U.S. have FXS.  Thereby is the CGG trinucleotide repeat segment in the FMR1 gene repeated in these individuals giving rise to patients considered carriers of either a normal, an intermediate, a premutated, or a fully mutated form of the FMR1 gene with associated potential health risks. The AmplideX Fragile X Dx and Carrier Screen Kit uses blood specimens from patients and determines the number of repeats of the CGG segment in the FMR1 gene.

Individuals with a full mutation typically have FXS, which is associated with developmental delays, learning disabilities, social and behavioral issues, intellectual disabilities and autism spectrum disorder. Women with a premutation have an increased risk of having a child with FXS as compared to women without a premutation. The number of women who have the Fragile X premutation is believed to be approximately 1 in 150 women. Men with a premutation will pass the premutation to their daughters only. Individuals with normal or intermediate levels of repeated CGG segments are currently thought to be asymptomatic for FXS or other fragile X-associated disorders.

In addition to aiding in the diagnosis of FXS and for carrier testing, this test can be used as an aid in the diagnosis of fragile X-associated disorders, including fragile X-associated tremor/ataxia syndrome, which is a movement and cognitive disorder that typically occurs in adults over age 50, and fragile X-associated primary ovarian insufficiency, a condition that is characterized by reduced function of the ovaries. In contrast, the AmplideX Fragile X Dx and Carrier Screen Kit is not intended for use in fetal diagnostic testing, the screening of eggs obtained for in-vitro fertilization prior to implantation, or stand‐alone diagnoses of FXS.

The FDA reviewed data for this test through the de novo classification process, a regulatory pathway for low- to moderate-risk devices of a new type. During this process, the FDA evaluated data from specimens collected at three clinical sites to assess the accuracy of the test. The data demonstrated that the diagnostic accuracy of the test is greater than 95%. Along with this authorization, the FDA is establishing criteria, called special controls, that test developers must meet for tests of this type, including requirements relating to labeling and performance testing. These special controls, when met along with general controls, provide a reasonable assurance of safety and effectiveness for tests of this type. This action also creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) pathway, whereby devices can obtain clearance by demonstrating substantial equivalence to a predicate device.

See here a short sequence on Fragile X Syndrome (FXS):

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Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.