Prenatal screening and diagnosis for fragile X syndrome
- Louise Wilkins-Haug, MD, PhD
Louise Wilkins-Haug, MD, PhD
- Section Editor — Prenatal Diagnosis and Genetics
- Professor of Obstetrics, Gynecology, and Reproductive Biology
- Harvard Medical School
Fragile X syndrome is an X-linked disorder and the most common inherited cause of intellectual disability . Both males and females can be affected. This topic will discuss preconception/prenatal screening and prenatal diagnosis for fragile X syndrome. The epidemiology, pathogenesis, clinical features, and postnatal diagnosis of the disorder are reviewed separately. (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)
FRAGILE X MUTATION
Gene — The fragile X mental retardation 1 gene (FMR1) is located on the X chromosome at Xq27.3 and most commonly has about 30 cytosine-guanine-guanine (CGG) trinucleotide repeats; the normal range is about 5 to 44 CGG repeats. In the general population, this region is stable and passes from generation to generation without significant alteration.
Pathogenesis — Fragile X syndrome is primarily caused by expansion in the number of CGG repeats within the FMR1 gene; deletions or point mutations within FMR1 account for only 1 percent of cases . Expansion of CGG repeats allows hypermethylation of FMR1, resulting in impaired transcription and reduced production of the fragile X mental retardation protein (FMRP), which adversely impacts prenatal and postnatal brain development.
As repeat size increases, stability decreases, and further increases in the number of repeats in the FMR1 region become likely. The lower and upper boundaries of repeat length are variably defined, but generally described as:
●Normal -- 5 to 44 CGG repeats
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- FRAGILE X MUTATION
- Risk for expansion
- Correlation with phenotype
- LABORATORY TESTING
- PRECONCEPTION AND PRENATAL SCREENING
- Candidates for screening
- Post-test counseling
- Follow-up testing
- PRENATAL DIAGNOSIS
- Interpretation of findings at prenatal diagnosis
- PRECONCEPTION REPRODUCTIVE OPTIONS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS