Non-Invasive Prenatal Testing, commonly referred to as NIPT, assesses the likelihood of a fetus having certain genetic conditions. This screening test utilizes a blood draw from the mother, which contains fragments of cell-free DNA (cfDNA) from the placenta. Fragile X Syndrome (FXS) is a common inherited cause of intellectual disability and developmental delay, resulting from a change in a single gene on the X chromosome. Expecting parents often seek to understand if routine NIPT screens for this specific condition.
How Standard NIPT Works and What It Screens For
NIPT analyzes cell-free DNA (cfDNA) fragments originating from the placenta that circulate in the mother’s bloodstream. These fragments represent the genetic material of the fetus. The primary goal of standard NIPT is to screen for aneuploidies, which are conditions caused by having an incorrect number of chromosomes. This includes the three most common autosomal trisomies: Trisomy 21 (Down Syndrome), Trisomy 18 (Edwards Syndrome), and Trisomy 13 (Patau Syndrome).
Standard NIPT also screens for abnormalities involving the sex chromosomes, such as Turner Syndrome (Monosomy X) or Klinefelter Syndrome (XXY). Some panels also include screening for microdeletion syndromes, which involve the loss of a small segment of a chromosome. Because NIPT is a screening tool, a positive result suggests an increased chance of a condition, but it is not a diagnosis. Any result indicating a high likelihood of an abnormality requires confirmation through a diagnostic procedure.
The Genetic Basis of Fragile X Syndrome
Fragile X Syndrome is caused by a different type of genetic change than the chromosomal imbalances that NIPT typically targets. FXS results from an expansion of a trinucleotide repeat sequence (CGG) within the FMR1 gene located on the X chromosome. This gene provides instructions for making the Fragile X Messenger Ribonucleoprotein (FMRP), a protein necessary for normal brain development and function. In most individuals, the FMR1 gene contains a stable number of CGG repeats (5 to 44).
Individuals who are premutation carriers have an unstable number of repeats (55 to 200). A full mutation, which causes FXS, occurs when the CGG repeat count exceeds 200 copies. This extensive expansion causes methylation, which silences the FMR1 gene and prevents the production of the FMRP protein. The absence of this protein leads to the characteristic cognitive and developmental features of the syndrome. Because FXS is a change in the length of a specific gene sequence, it requires a different molecular testing method than the counting strategy used by standard NIPT.
Fragile X Carrier Screening and Expanded NIPT Options
FXS is primarily assessed through carrier screening, performed on prospective parents, usually the mother, before or early in pregnancy. Carrier screening determines if a parent carries an FMR1 gene expansion (pre-mutation) that puts the fetus at risk for the full mutation. This direct DNA test precisely counts the number of CGG repeats in the mother’s FMR1 gene. If a woman is identified as a pre-mutation carrier, the risk of passing the full mutation to her child is calculated based on the size of her pre-mutation.
Some specialized laboratories offer expanded NIPT options that attempt to screen for single-gene disorders, including FXS, directly in the fetus. These expanded panels use complex technology to analyze fetal cfDNA for the FMR1 gene expansion. However, these tests are not yet standard practice and have limitations; they often only determine if a pre-mutation or full mutation is present, but may not determine the exact number of CGG repeats. Carrier screening remains the most commonly utilized initial step for FXS risk assessment.
Diagnostic Testing for Fragile X
When screening tests indicate a high likelihood of the fetus having Fragile X Syndrome, definitive diagnostic testing is recommended. This requires obtaining a sample of fetal genetic material through an invasive procedure. The two main diagnostic procedures are Chorionic Villus Sampling (CVS), performed earlier in pregnancy, and Amniocentesis, performed later. CVS involves taking a small sample of placental tissue, while Amniocentesis collects a sample of the amniotic fluid.
The fetal DNA from these samples is tested using specific molecular techniques, such as Polymerase Chain Reaction (PCR) and Southern blot analysis. These methods precisely determine the exact number of CGG repeats in the FMR1 gene of the fetus. This direct measurement confirms the presence of a full mutation (over 200 repeats) and provides information about the gene’s methylation status. These diagnostic tests provide a conclusive answer necessary for informed decision-making.