Prevalence and instability of fragile X alleles: implications for offering fragile X prenatal diagnosis.
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.


CONCLUSIONS
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.
Cronister
Amy
A
Genzyme Genetics Genetic Services, Philadelphia, Pennsylvania, USA. amy.cronister@genzyme.com
Teicher
Jennifer
J
Rohlfs
Elizabeth M
EM
Donnenfeld
Alan
A
Hallam
Stephanie
S
D000293:Adolescent; D000328:Adult; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000453:epidemiology / Q000235:genetics*; D050172:Genes, X-Linked / Q000235:genetics; D006580:Genetic Carrier Screening; D005817:Genetic Counseling; D005820:Genetic Testing; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D015995:Prevalence; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D014481:United States / Q000453:epidemiology
D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human