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Saint Mary’s Hospital Manchester Centre for Genomic Medicine The Inheritance of the Fragile X Gene Information For Patients 1 Introduction This leaflet describes the way the Fragile X (FraX) gene is passed on in families. It also describes the different forms of the gene and the effect these different forms can have. It does not include detailed information about the symptoms of Fragile X syndrome or advice for management. The Fragile X Society has produced excellent booklets about many aspects of the condition in a variety of languages (www.FragileX.org.uk). Inheritance Fragile X is a genetic inherited and is caused by an alteration (sometimes called a change, mutation or expansion) in the Fragile X gene. Genes are the instructions our bodies use to grow and develop. All of our genes are packaged on structures called chromosomes. The Fragile X gene is found on the X chromosome. Women have two X chromosomes and men have one X and one Y chromosome. This means that women have two copies of the Fragile X gene while men have only one. When men have children they pass on their X chromosome to all their daughters and their Y chromosome to all their sons. When women have children they pass on one or other of their X chromosomes to each of their children. The Fragile X gene The Fragile X gene varies in size and, based on this, is described as normal, premutation or full mutation. Below we describe how the size of the Fragile X gene affects men and women differently and how each might pass the gene on. 1. Men who have a Full Mutation Men who inherit a full mutation will have Fragile X syndrome. The range and severity of symptoms varies widely and cannot be predicted by a genetic test. Men with a full mutation are usually infertile. If they do have children, their daughters will all carry a premutation but their sons will not be affected or be carriers of Fragile X syndrome. 2 2. Women who have a Full Mutation Only about 50% or 1 in 2 women who have inherited a full mutation have symptoms of Fragile X syndrome. This is because they also have a second (usually normal) copy of the fragile X gene which can compensate. Women who are affected usually experience less severe symptoms than men who are affected, but this is not always the case. The genetic test cannot tell us whether or not a woman with the full mutation will have symptoms of Fragile X syndrome. If a woman with a full mutation has children, there is a 50% (1 in 2) chance of her passing on the X chromosome with the full mutation to her child (see diagram 1). What this means for the child will depend on whether they are male or female (see below). Diagram 1: Possible outcomes when a woman with a full mutation has children Male Partner – Non Carrier Female with a Full Mutation X Y 1 in 4 chance of a daughter without a full mutation (unaffected) XX 1 in 4 chance of a daughter with a full mutation (50% or 1 in 2 of these will have symptoms of Fragile X) 3 1 in 4 chance of a son without a full mutation 1 in 4 chance of a son with a full mutation (unaffected) (affected) 3. Men who have a Premutation Men who have a premutation do not have Fragile X syndrome (but some studies suggest there may be a link to some mild symptoms such as anxiety in social situations). When a man passes on a premutation it remains the same size. A man with a premutation will pass on his X chromosome (carrying the premutation) to all of his daughters, but his Y chromosome (without a Fragile X gene) to all of his sons (see diagram 2). This means a man with a premutation is not at risk of having a child with Fragile X syndrome, but his grandchildren, born to his daughters, could be affected. A proportion of men who have a premutation develop problems with movement, balance and/or memory later on in life. The chance of this happening increases with age. The majority of men with a premutation will have some problems over age 70. This condition is called FXTAS (Fragile X Tremor Ataxia Syndrome) and although it is due to the Fragile X gene, the symptoms are very different to Fragile X syndrome. If you have concerns regarding symptoms experienced by you or a family member, either get in touch with your genetics doctor/ counsellor or discuss your concerns with your GP. A link between being a premutation carrier and thyroid problems has been described. If you have never had a check of your thyroid function, your GP could arrange testing for you. 4 Diagram 2: Possible Outcomes when a man with a Premutation has children Male with a Premutation Female Partner – Non Carrier X Y XX 1 in 2 chance of a daughter 1 in 2 chance of a son (all daughters unaffected (all sons will be unaffected but will have a premutation) non-carriers) 5 4. Women who have a Premutation Women who have a premutation do not have Fragile X syndrome (but some studies suggest there may be a link to some mild symptoms such as anxiety in social situations). A woman with a premutation has a 50% (1 in 2) chance of passing on the premutation to each of her children. When passed on by a woman a premutation will either stay the same size or may get bigger and become a full mutation. If a woman passes on a premutation unchanged, her child (male or female) will be a carrier of a premutation but will not have Fragile X syndrome. If the premutation becomes a full mutation when it is passed on to a son, the son will be affected by Fragile X syndrome. If the premutation becomes a full mutation when it is passed to a daughter, there is a 50% (1 in 2) chance that she will have symptoms of Fragile X syndrome (see diagram 3). It is not possible to accurately predict the chance of a gene changing from a premutation to a full mutation when it is passed on, although in general the larger the premutation the more likely it is to increase into the full mutation range when it is passed on. Some women with a premutation can have fertility problems and/or an earlier menopause than usual. Women who are concerned about their fertility can be referred to a doctor in Reproductive Medicine at Saint Mary’s Hospital for an assessment of their ovarian function. Women who are concerned about possible early menopausal symptoms can be referred to an Endocrinologist based at Christie Hospital for an assessment. A small proportion of women with a premutation develop problems with movement, balance and/or memory associated with FXTAS similar to those seen in a larger proportion of men with a premutation (see section 3). A link between being a premutation carrier and thyroid problems has been described and if you have never had a check of your thyroid function it would be advisable to ask your GP for at least a one-off test. 6 Diagram 3: Possible Outcomes when a woman with a Premutation has children Male Partner Female with a Non CarrierPremutation Carrier X Y 1 in 4 chance of a daughter with 2 normal X chromosomes XX 1 in 4 chance of a son with a normal X chromosome 1 in 4 chance of a daughter with EITHER a premutation OR a full mutation (see text section 4) 7 1 in 4 chance of a son with EITHER a premutation OR a full mutation (see text section 4) The Fragile X Society The Fragile X Society provides information and support for individuals with Fragile X and their families. You can contact them at the following address: The Fragile X Society Rood End House 6, Stortford Road Great Dunmow Essex CM6 1DA Tel: 01371 875100 E-mail: [email protected] Website: www.fragilex.org.uk 8 Zero Tolerance Policy We are committed to the well-being and safety of our patients and of our staff. Please treat other patients and staff with the courtesy and respect that you expect to receive. Verbal abuse, harassment and physical violence are unacceptable and will lead to prosecutions. Suggestions, Concerns and Complaints If you would like to provide feedback or have a complaint there are several options available to you: • Speak to the ward or department manager – they may be able to help straight away. • Contact our Patient Advice and Liaison Service (PALS) – Tel: (0161) 276 8686 e-mail: [email protected]. Ask for our information leaflet which can also be found in the hospital. • Through the NHS Choices website www.nhs.uk by clicking on the ‘Comments’ section. We welcome your feedback so we can continue to improve our services. 9 Notes 10 11 TIG 102/11 Produced September 2014 Review 12 Date September 2016 (SF Taylor CM12825)