Fragile X

Fragile X syndrome is the most common known inherited cause of intellectual disability and autism. Features of fragile X syndrome vary widely but can include mild to severe cognitive delays, seizures, behavioral differences such as perseverative speech and hand flapping, and characteristic facial features such as large ears and a long face. About 1 in 4,000 males and 1 in 5,000 to 8,000 females has fragile X syndrome. The molecular basis for fragile X syndrome is an increased number of trinucleotide CGG repeats in the 5′ promoter region of the FMR1 gene. FMR1 alleles can be further categorized based on the number of CGG repeats, and premutation alleles may expand from parent to child to a full mutation that can cause features of fragile X syndrome. In addition, people with premutations may develop fragile X-associated Tremor/Ataxia Syndrome (FXTAS) and women may develop fragile X-associated Primary Ovarian Insufficiency (FXPOI).

Table 1: Categories of triplet repeat mutations in the FMR1 gene.

REPEAT NUMBER ALLELE CATEGORY CLINICAL FEATURES LIKELIHOOD TO EXPAND
<45 Normal None Stable
45-54 Intermediate None Small likelihood to expand by usually a small number of repeats
55-200 Premutation FXTAS symptoms over age 50 (46% of males and 17% of females); FXPOI (15-20% of females) Unstable; likelihood varies based on total repeat number and AGG interruptions; may expand to full mutation
>200 Full mutation Fragile X syndrome Unstable
Fragile X Clinical and Research Consortium
www.fxcrc.org
FRAXA Research Foundation
www.fraxa.org
10 Prince Place
Newburyport, MA 01950
Phone: 978-462-1866
E-mail:info@fraxa.org
Genetic and Rare Diseases Information Center
www.rarediseases.info.nih.gov/gard
P.O. Box 8126
Phone: 888-205-2311
E-mail:rarediseases@info.nih.gov
National Fragile X Foundation
www.fragilex.org
1615 Bonanza St. Suite 202
Walnut Creek, CA 94596
Phone: 800-688-8765
E-mail:natlfx@FragileX.org
National Society of Genetic Counselors
www.nsgc.org
330 N. Wabash Avenue, Suite 2000
Chicago, IL 60611
Phone: 312-321-6834
E-mail:nsgc@nsgc.org
The Fragile X Society (United Kingdom)
www.fragilex.org.uk
Rood End House, 6 Stortford Road
Great Dunmow, Essex CM6 1DA
Phone: 00 44 (0)1371 875100
E-mail:info@fragilex.org.uk