Fragile X syndrome

Inheritance

Does the CGG trinucleotide expansion get bigger in each generation in a family with fragile X syndrome?

Fragile X syndrome is an X-linked disorder that follows an inheritance pattern known as the Sherman Paradox. This phenomenon is also referred to as anticipation, where symptoms of a hereditary disease occur earlier (at a younger age) and can be more severe in the next generation. The first CGG trinucleotide mutation that results in a premutation size of 55 to 200 repeats occurs in one generation. As it passes from generation to generation, the premutation can increase in number of repeats (particularly in women). The larger the premutation size, the more unstable it becomes, and the more likely it is to expand to a full mutation in subsequent generations.

For example, a grandfather who has 60 CGG repeats and no FMR1-associated health issues passes on his FMR1 gene premutation to his daughter. In his daughter, the premutation has expanded to 65 repeats in her FMR1 gene; she experiences the symptoms of early menopause associated with FMR1-related primary ovarian insufficiency that can occur in women with the premutation. This daughter has a son, and the premutation expands further and becomes a full mutation of more than 200 repeats in his FMR1 gene. Therefore, her son would have fragile X syndrome and would show some or many of the characteristics associated with the syndrome. For information on what laboratories offer testing for the repeat number in the FMR1 gene, please visit GeneTests.

Sherman, S. L., Morton, N. E., Jacobs, P. A. and Turner, G. (1984), The marker (X) syndrome: a cytogenetic and genetic analysis. Annals of Human Genetics, 48: 21–37. doi: 10.1111/j.1469-1809.1984.tb00830.x

http://www.ncbi.nlm.nih.gov/pubmed/6712153?dopt=Abstract

Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: Diagnostic and carrier testing. Genetics in Medicine. 2005;7(8):584-587. doi:10.1097/01.GIM.0000182468.22666.dd.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110946/#b1-16247297

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