Genetic Testing for Fragile X.

Ask the Expert provides research-based answers to practice questions submitted by JSPN readers. Where possible, evidence from research is used to support the experts' recommendations.

Question: I have a friend who has a son with fragile X syndrome. She would like to have her 6-year-old daughter tested to see if she is a carrier of fragile X. What is involved in fragile X testing?

Cynthia A. Prows replies: Genetic testing of people suspected of having fragile X is advocated, but genetic testing to determine carrier status of pediatric siblings/offspring of people with fragile X syndrome is controversial. This column will provide an overview of the genetics and clinical features of fragile X syndrome, genetic testing capabilities, and the impact of fragile X and genetic testing on families. Anne Lovell's response related to the controversies specific to carrier testing in children will follow.

Genetics of Fragile X Syndrome

Fragile X is the most commonly inherited condition associated with mental retardation (Hagerman, 1997a). In 1991, the genetic code of the fragile X mental retardation 1 gene (FMR1) located on the X chromosome was discovered, and the unique mutation (Figure 1) responsible for the clinical features was determined (Rousseau et al., 1991).

[Figure 1 ILLUSTRATION OMITTED]

Approximately 80% to 85% of males who inherit the full mutation will have fragile X syndrome with mental retardation, while about 50% of females will have some clinical features but not necessarily mental retardation (Hagerman, 1997b). Males with a premutation (a mutation not large enough to cause symptoms) are referred to as unaffected/normal transmitting males. They do not have fragile X syndrome. Because they only have one X chromosome, however, which they transmit to all their daughters, and one Y chromosome, which they transmit to all their sons, all their daughters but none of their sons will be carriers of the premutation (Figure 2A).

[Figure 2 ILLUSTRATION OMITTED]

Females with the premutation do not have fragile X syndrome, but the premutation has the propensity to expand into a full mutation when transmitted from a female to her offspring (Moutou, Vincent, Biancalana, & Mandel, 1997) (Figure 2B). The full mutation usually is accompanied by abnormal methylation (methyl groups attach to components of the gene), which essentially turns off the gene and thus protein production. The reduced or absent protein product (FMRP) is responsible for the clinical features of fragile X syndrome (Hagerman, 1997b).

Approximately 50% of females who inherit a full mutation have clinical features of fragile X syndrome. It is important to remember that females have two X chromosomes. During early embryogenesis, one X chromosome normally is turned off (inactivated) in every cell. This inactivation process is random. Therefore, the presence or absence of effects of a full mutation in FMR1 is affected by the proportion of cells in which…