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The Fragile X Syndrome Fragile X syndrome is a challenging disorder that puts fear into the heart of anyone brave (or foolish) enough to provide a brief summary. It seems to flout every rule about X-linked inheritance, has a confusing variety of clinical features and is very common.

What is special about the genetics of Fragile X syndrome? The gene responsible, FMR1, is on the X chromosome. On that basis, you would expect that males would be affected and that female carriers would not. However, that reasonable expectation is incorrect. The FMR1 gene has a cluster of three base pairs (-C-G-G-) that is repeated many times. The number of repeats varies between 5–44 in the normal healthy population. An FMR1 gene with a repeat number in the normal range is passed on unchanged to children. However, people with 55–200 repeats are at risk of problems. Women with FMR1 repeats in this range are at risk of premature ovarian failure, and both men and women are at risk of developing late-onset ataxia and tremor. These are not inevitable outcomes, and the majority of such people remain asymptomatic. It is important to note that intellectual disability is not noted in people with FMR1 repeats in this range. There are important implications for relatives. When an FMR1 repeat in the 55–200 range is passed from mother to child, it can increase in size; this does not occur when transmitted by the father. This does not happen with every maternal transmission, but becomes more likely as the repeats get larger. For this reason, repeat numbers in this range are referred to as ‘pre-mutations’. If the expanded repeat size in the child is less than 200, the child is also at risk of premature menopause (if female) and ataxia/tremor, but not of intellectual disability. But what if the repeat size exceeds 200? An FMR1 repeat size that is greater than 200 is called a ‘full mutation’. Males with a full mutation have intellectual disability of varying degree — the ‘Fragile X syndrome’. About half of the females with a full mutation have mild intellectual disability, with the remainder being likely to demonstrate learning difficulties or some disturbance of mental health.

The genetics of Fragile X syndrome is unusual in that a healthy man can have a pre-mutation, will pass the pre-mutation to his daughter, and she may have an affected son with a full mutation. It is also unusual that such a high proportion of female carriers of a full mutation have intellectual disability. To complete the story, there is an ‘intermediate’ range of FMR1 repeats, that is, 45–54. Intermediate repeat numbers are not associated with any of the disorders described earlier, but there is a small chance that an intermediate repeat will expand into a pre-mutation when transmitted by a mother.

Which patients should be tested for Fragile X syndrome? Given the variety of clinical features caused by an abnormal FMR1 gene, and the potential significance for relatives, it can be challenging to know who to test. Indications for diagnostic Fragile X testing In children or adults


Intellectual disability Global developmental delay Autism spectrum disorder

In women under the age of 40


Irregular periods or impaired fertility with raised FSH levels

In older adults (over 50 years)


Late-onset tremor and ataxia

The purpose of testing in these situations is to make a diagnosis in an affected person. There is another important group who should be offered testing: unaffected people with a blood relative who has been shown to have an abnormal FMR1 repeat. Such testing can clarify their risk of having affected children or grandchildren.

What does testing for Fragile X syndrome involve?

Who should manage testing for Fragile X syndrome?

The earliest assay was a chromosome study. An X chromosome with a full mutation is structurally fragile at the location of the FMR1 repeats and can break apart at that point (thereby explaining the name of the disorder). The laboratory now counts the number of FMR1 repeats directly (up to 200); detection of full mutation requires a second method. The test is done on a sample of blood collected into EDTA.

The Fragile X syndrome is common and the clinical indications for testing are broad. Approximately 1:4,000 males has the disorder, and approximately 1:200 females carries a pre-mutation. Hence, any clinician caring for patients with the clinical features previously described should consider testing as appropriate.

The analysis and reporting gets complex if there is an increased probability of the patient having Fragile X syndrome, for example, family history of Fragile X, or testing an affected woman. The story can be further complicated by the patient (male or female) having a mixture of cells with pre-mutations and full mutations. The laboratory can disentangle these various possibilities and arrange the necessary testing, but only if clinicians provide clinical details on the request form. Please assist us by providing as much clinical information as possible. This will help us to determine the most useful test and to give you the most useful result. Testing is available through Douglass Hanly Moir Pathology. There is a Medicare rebate for diagnostic testing in patients with features, such as intellectual disability, ataxia, neurodegeneration or premature ovarian failure, that are consistent with an FMR1 mutation. A rebate is also available for testing an unaffected person with a relative who has an FMR1 mutation. The MBS rebate is not available outside of these criteria, for example, for preconception screening.

However, once an intermediate, pre-mutation or full mutation has been identified, the genetic implications for the wider family become complex on medical, emotional and social grounds. Patients should be forewarned of this possibility before the test is performed. The management of the extended family is best overseen by clinical genetics experts, and referral of the family for genetic counselling is strongly recommended. This brief article does not address many of the clinical and genetic details regarding Fragile X syndrome. For further information please refer to the following: References ÎÎ Saul RA, Tarleton JC, FMR1- Related Disorders, GeneReviews®, https://www.ncbi. books (Keywords FMR1 related disorders) (Accessed February 2017) ÎÎ American College of Medical Genetics and Genomics, ACMG Standards and Guidelines, (Keywords Fragile X Guidelines) (Accessed February 2017) ÎÎ Health Centre for Genetics Education, Fragile X Syndrome, www.genetics. (Keywords Fragile X Fact Sheet) (Accessed February 2017) ÎÎ The Fragile X Association of Australia, (Accessed February 2017)

This article was published in March 2017 and has been reproduced with the permission of Professor Graeme Suthers (Director of Genetics - Sonic Healthcare).

Professor Graeme Suthers  BSc (Med), MBBS, PhD, FRACP, FRCPA, GAICD Director – Sonic Genetics Australia Sonic Genetics is headed by Professor Graeme Suthers. A clinical geneticist and a genetic pathologist, Professor Suthers is one of Australia’s most respected experts in the field of genetics. With an outstanding career and deep experience in genetics, healthcare and research, he is nationally and internationally recognised for his expertise in genetic disorders, testing and clinical service provision. Professor Suthers has been closely involved in the development of software solutions for specialty genetic services and in the evaluation of healthcare interventions to promote genetic services of the highest quality and utility to patients, families and managing clinicians.

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Version 1 | 2017

Testing for Fragile X syndrome | Prof Graeme Suthers  

What is special about the genetics of FXS? Which patients should be tested? What does testing involve? Who should manage testing for FXS? 2...

Testing for Fragile X syndrome | Prof Graeme Suthers  

What is special about the genetics of FXS? Which patients should be tested? What does testing involve? Who should manage testing for FXS? 2...