1. SECTIONS:
2. preface & acknowledgements
3. genetics at a glance
4. contacts, support & testing
5. testing & pregnancy
6. newborn screening
7. cancer in the family
8. cardiovascular conditions
9. chromosomal conditions
10. clotting & bleeding conditions
11. cystic fibrosis
12. diabetes
13. fragile X syndrome and other causes of developmental delay
14. haemoglobinopathies
15. hereditary haemochromatosis
16. neurofibromatosis
17. neurological conditions
18. psychiatric conditions
19. genetics in practice
20. emerging genetic technologies
21. glossary

Genetics

 

1. Fragile X syndrome follows an X-linked pattern of inheritance.
   
2. However, due to the type of genetic alteration involved, the pattern of X-linked inheritance is atypical.
   
3. It is caused by a mutation in a gene on the X chromosome (the FMR1 gene: fragile X mental retardation 1). The FMR1 gene codes for a protein, FMRP, which is thought to be necessary for normal neurological functioning.
   
4. Fragile X syndrome results from an increase in the number of copies of a tri-nucleotide sequence within
   the gene (see Table 1). Most people have between 6 and 54 repeats, with an average of 30. Copy numbers between 55 and 200 or 230 (depending on how it is reported by the laboratory) are said to
   be ‘premutations’ and copy numbers of 200 or 230 and above are said to be ‘full mutations’. Genes with premutations and full mutations contain an expansion. Full mutations cause FMRP to be switched off, resulting in an individual having fragile X syndrome.

 

Inheritance pattern

1. The size of the expansion in the FMR1 gene is unstable and can change through generations. Both men and women with an expansion may pass it on to their children:
2. Mother to child transmission is unstable, and the expansion may increase in size
   
3. Mothers of affected males carry either a premutation or a full mutation
   
4. Father to daughter transmission is stable within a small variation for premutations; that is, the expansion will not increase to a full mutation
   
5. There is limited data on men with full mutations; however, it appears that daughters usually inherit
   a premutation from their affected fathers
6. Women who are carriers of a premutation or a full mutation have a 50% chance of passing it on to each
   of their children.
   
7. The risk of a female premutation carrier having a child with the full mutation is related to the size of her premutation.
   
8. Men pass a premutation or a full mutation on to all their daughters but to none of their sons, as the sons receive only their father’s Y chromosome.

 

Table 1

Repeat numbers and variable presentation of fragile X syndrome

 

1. A male diagnosed with fragile X syndrome could have inherited this from:
2. A mother with a full mutation

OR

1. A mother with a premutation
2. Family studies are likely to identify individuals with premutations and may identify individuals with full mutations. Genetic counselling is important and allows families to make informed decisions about family planning (see Contacts, support and testing).
   
3. It is difficult to distinguish between a normal version of the gene and a small premutation.
   
4. The number of repeats of an intermediate size (so called ‘grey zone’ in the upper end of normal range)
   can change into a premutation when passed on to children.

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