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Prevalence and Instability of Fragile X Alleles

Implications for Offering Fragile X Prenatal Diagnosis

From ¹Genzyme Genetics Genetic Services, Philadelphia, Pennsylvania; and ²Genzyme Genetics Molecular Diagnostic Laboratory, Westborough, Massachusetts.

OBJECTIVE: To document fragile X allele frequencies in a national referral population and evaluate CGG repeat expansion in mother-offspring transmissions.

METHODS: Fragile X DNA analysis by Southern blot and polymerase chain reaction was completed for 14,675 women, aged 18 years or older, and 238 mother-offspring pairs between January 1999 and June 2004. Carrier frequencies were compared between groups referred for different clinical indications. Direct comparison of the FMR1 gene CGG repeat size in mother-offspring pairs determined intermediate and premutation allele stability.

RESULTS: Intermediate fragile X alleles (45–54 CGG repeats) occurred in 257 (1 in 57). The combined total number of patients with a premutation (55–200 CGG repeats) or full mutation (more than 200 CGG repeats) numbered 208 (1 in 71). One in 3.5 women with a family history of fragile X and 1 in 10 with premature ovarian failure had a FMR1 mutation. This compared with 1 in 86 for those with a family history of mental retardation and 1 in 257 for women with no known risk factors for fragile X. Among 238 mother-offspring pairings, the smallest allele to expand to a full mutation in one generation contained 60 CGG repeats. Although 6.6% (4 of 60) of intermediate repeat alleles did expand, none jumped to a clinically significant full mutation–sized allele.

CONCLUSION: Based on these data and other published literature, offering invasive prenatal diagnosis for fragile X syndrome is not indicated for women with intermediate alleles. Invasive prenatal diagnosis is warranted for those women with a fragile X allele containing 55 or more CGG repeats.

LEVEL OF EVIDENCE: III

This article has been cited by other articles:

				Fragile X Allele Testing: When Is Prenatal Testing Indicated? Journal Watch (General), April 10, 2008; 2008(410): 2 - 2. [Full Text]