Education And Debate

Case finding for the fragile X syndrome and its consequences

BMJ 1997; 315 doi: (Published 08 November 1997) Cite this as: BMJ 1997;315:1223
  1. Gillian Turner (, directora,
  2. Hazel Robinson, coordinatorb,
  3. Samantha Wake, genetic counsellora,
  4. Susan Laing, data coordinatorb,
  5. Michael Partington, clinical geneticista
  1. a Fragile X Program, Hunter Genetics, PO Box 84, Newcastle, NSW 2298, Australia
  2. b Fragile X Program, Sydney Children's Hospital, Sydney, New South Wales, Australia
  1. Correspondence to: Dr Turner
  • Accepted 11 June 1997


The fragile X syndrome is a cause of mental disability in both males (1/4000 births) and females (1/8000 births).1 Diagnosis is often delayed into mid-childhood or beyond, and in some families it is never made. The inheritance pattern is X linked, which means that members of the extended family are at risk of being carriers. These individuals have a right to information and counselling in making their own choices about reproduction. In New South Wales a programme of active case finding has been in place for 10 years.2 We describe this programme and look at the outcome and possible future directions.

Fragile X syndrome

Males with fragile X syndrome (fig 1) need extra help at school, protected employment later, and are not usually able to live independently. Affected females have much milder learning difficulties and fewer obvious clinical features; half of those with the full mutation are not recognised as disabled but most have some learning difficulties.

Although the syndrome is X linked, the underlying genetic mechanism is not straightforward. The function of the gene product—the FMR-1 protein—is unknown.3 The gene promoter region contains a CCG repeat island with a repeat length, normally in the 20–40 range, that is passed down from generation to generation. The repeat length may slowly increase over generations and become progressively more unstable, probably because of “slippage” (inaccurate duplication that occurs in stretches of identical repeats). An elongation of 54 or so repeats can suddenly expand to more than 200 in one generation.4 This large change, or full mutation, switches off the promoter and stops gene production. Both sexes may have smaller expansions or premutations of 54–200 repeats. These people are normal but the women have an earlier menopause5; they are called “normal transmitting” males or females. Expansion or amplification into the …

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