Non-Invasive Prenatal Testing (NIPT) has become a common method for screening during pregnancy. This screening method is popular because it requires only a maternal blood sample, posing no risk to the pregnancy. Parents often wonder if this comprehensive blood test can also detect Fragile X Syndrome (FXS), which is a common inherited cause of intellectual disability. The answer requires an understanding of how NIPT works and the unique genetic mechanism that causes Fragile X Syndrome.
Understanding NIPT and Standard Screening
Non-Invasive Prenatal Testing is a screening method that analyzes cell-free fetal DNA (cfDNA) circulating in the pregnant person’s bloodstream. These small fragments of DNA originate from the placenta and are generally identical to the fetus’s DNA. The standard application of NIPT is to screen for common aneuploidies, which are conditions caused by an abnormal number of chromosomes. The primary targets include Trisomy 21 (Down syndrome), Trisomy 18 (Edwards syndrome), and Trisomy 13 (Patau syndrome). NIPT works by counting the proportion of DNA fragments corresponding to these specific chromosomes to detect an excess or deficiency. It can also screen for abnormalities involving the sex chromosomes, such as Turner syndrome or Klinefelter syndrome.
Fragile X Syndrome: The Genetic Basis
Fragile X Syndrome is a genetic neurodevelopmental disorder that is a frequent cause of inherited intellectual disability. The condition is caused by a mutation in a single gene called the Fragile X messenger ribonucleoprotein 1 gene, or FMR1. This gene is located on the X chromosome and is responsible for making a protein needed for normal brain development.
The mutation is a unique type of genetic change known as a trinucleotide repeat expansion of the CGG sequence. Most people have fewer than 45 CGG repeats, which is considered a normal allele. Individuals with a “premutation” have a repeat count between 55 and 200, which can put their children at risk for the full syndrome. The full mutation, which causes Fragile X Syndrome, involves more than 200 CGG repeats. This excessive expansion leads to the silencing of the FMR1 gene, meaning the necessary protein is not produced. This mechanism of a massive, localized repeat expansion is fundamentally different from the extra or missing whole chromosomes that NIPT is designed to detect.
NIPT and Fragile X: Coverage and Limitations
Fragile X Syndrome is generally not included in the standard NIPT panels offered to pregnant people. Detecting the specific number of trinucleotide repeats within a small region of a single gene requires a different and more technically challenging form of genetic analysis. Some commercial laboratories have begun offering expanded NIPT panels that include screening for a limited number of single-gene disorders, which can sometimes include FXS.
However, the technology’s sensitivity for detecting this specific type of repeat expansion is significantly limited when analyzing cfDNA. The massive CGG repeat expansions that cause FXS are typically not found in the cell-free DNA fragments that NIPT analyzes. Even when FXS is included in an expanded panel, it remains a screening test, which means a positive result only suggests an increased risk. Any high-risk result from an NIPT screening must be confirmed with a definitive diagnostic test. The complex nature of the FMR1 gene’s repeat expansion makes it difficult for NIPT to accurately assess the fetal status, especially in cases where the mother is a premutation carrier.
Definitive Prenatal Testing for Fragile X
Since NIPT is not a definitive tool for Fragile X Syndrome, other established methods are used to determine risk and provide a diagnosis. Carrier screening is a blood test often performed before or early in pregnancy to check the mother’s FMR1 gene status. This testing precisely counts the number of CGG repeats in the mother’s DNA to identify if she is a carrier of an intermediate or premutation allele. Identifying a mother as a premutation carrier is the primary indicator for needing further testing, as the premutation can expand to the full mutation when passed to the child.
If the mother is identified as a carrier, or if there is a known family history of FXS, invasive diagnostic procedures are available during pregnancy. These tests obtain fetal cells directly for a definitive diagnosis.
Diagnostic Options
- Chorionic Villus Sampling (CVS), which is performed earlier in the pregnancy by sampling the placenta.
- Amniocentesis, which involves analyzing amniotic fluid later in the pregnancy.
Both procedures analyze the fetal DNA directly to provide an exact count of the CGG repeats in the FMR1 gene, confirming the presence or absence of the full mutation.