Non-invasive prenatal testing (NIPT) has revolutionised prenatal screening by providing expectant parents with a highly accurate and safe method of detecting genetic conditions in the fetus. However, not all NIPTs are created equal. Understanding the difference between basic and extended NIPT is crucial for making informed decisions during pregnancy. In this article, we will explore the key distinctions between these two types of NIPT and the implications they have for prenatal care.

What is Basic NIPT?

Basic NIPT focuses primarily on detecting common chromosomal aneuploidies. These include:

1. Trisomy 21 (Down syndrome): The most frequently occurring aneuploidy, characterised by an extra copy of chromosome 21. This condition is associated with a spectrum of developmental delays, intellectual disabilities, and physical features such as hypotonia, a flat facial profile, and a single palmar crease.
2. Trisomy 18 (Edwards syndrome): Associated with severe developmental delays and physical abnormalities.
3. Trisomy 13 (Patau syndrome): A rare but severe condition linked to profound developmental issues.
4. Many basic NIPTs include sex chromosome aneuploidies, conditions that affect the number of X or Y chromosomes, such as Turner syndrome (45,X) and Klinefelter syndrome (47,XXY).

Basic NIPT typically provides results with high sensitivity and specificity for these conditions. Among the conditions tested, NIPT has the highest sensitivity and specificity for trisomy 21, and its diagnostic performance is lower for trisomy 18 and trisomy 13. However, sex chromosome aneuploidies are known to have a relatively low positive predictive value (PPV), which means they may result in a high false positive rate.

What is Extended NIPT?

Extended NIPT goes beyond the common aneuploidies to screen for additional genetic conditions. This comprehensive approach includes three distinct levels of genetic screening:

Aneuploidies

As with basic NIPT, extended screening includes common trisomies (Down, Edwards, and Patau syndromes) and sex chromosome aneuploidies, but it also assesses rarer autosomal aneuploidies affecting other chromosomes. Importantly, checking for additional syndromes does not compromise the performance of the test for trisomy 21 (Down syndrome).

Microdeletions

Microdeletions are variants of structural chromosomal anomalies. They involve the loss of small but critical segments of DNA within a chromosome. These missing segments can contain multiple important genes, leading to severe and sometimes life-altering conditions. Some microdeletions are more severe than Down syndrome (trisomy 21). Examples of microdeletion syndromes are:

• 22q11.2 deletion syndrome (DiGeorge syndrome): Associated with heart defects, immune dysfunction, and developmental delays.
• Cri-du-chat syndrome: Caused by a deletion on chromosome 5, leading to intellectual disability and distinctive physical features.
• Prader-Willi and Angelman syndromes: Resulting from deletions on chromosome 15, with unique clinical presentations.

Single-Gene Disorders (monogenic syndromes)

Most genetic syndromes in children are related to monogenic (single-gene) disorders. These tests screen for mutations in individual genes that may cause de novo or hereditary conditions. Many of these single-gene disorders can be associated with physical and/or intellectual disabilities. Examples include:

• Achondroplasia: A de novo mutation resulting in a common form of dwarfism.
• Apert syndrome: A genetic condition characterised by craniosynostosis (premature fusion of skull bones), distinctive facial features, and fusion of fingers, often leading to functional and aesthetic challenges.
• Noonan syndrome: A condition with features like heart defects, developmental delays, and distinct facial characteristics.
• Cystic fibrosis: A hereditary condition affecting the respiratory and digestive systems.

Benefits of Extended NIPT

Extended NIPT provides a more detailed assessment of the fetus’s genetic health. It is particularly advantageous in the following scenarios:

• High-risk pregnancies: For parents with a family history of genetic conditions, prior pregnancies affected by genetic disorders, advanced maternal and/or paternal age, or IVF pregnancies, extended screening can offer invaluable insights.
• Unexplained ultrasound findings: When ultrasound findings or abnormalities suggest a potential genetic condition, extended NIPT can help clarify the diagnosis.
• In cases of increased nuchal translucency (high NT), when parents prefer to avoid invasive diagnostic tests such as CVS or amniocentesis and opt for NIPT, it is essential to consider the limitations of basic NIPT. Basic NIPT does not screen for many genetic syndromes associated with increased NT. In such situations, extended NIPT can be a preferred option, as it includes screening for monogenic conditions like Noonan syndrome, Kabuki syndrome, severe skeletal dysplasias, and other syndromes, as well as microdeletions such as 22q11.2 deletion syndrome (DiGeorge syndrome).
• An additional test after normal CVS or amniocentesis results for common trisomies (Down, Edwards, and Patau syndromes) and microdeletions/microduplications is often recommended. Unfortunately, for many parents, the standard invasive diagnostic test does not check for most genetic syndromes. To check for monogenic syndromes (single gene disorders), someone needs to have a test called exome or whole genome sequencing (WGS). Extended NIPT, looking for selected monogenic syndromes, will have an additional value in those cases. It cannot replace the exome but will screen for common and serious monogenic conditions.
• Reproductive planning: Knowledge of single-gene disorders or microdeletions can inform reproductive decisions, such as choosing between continuing or terminating a pregnancy, planning for specialised care or interventions post-birth, and understanding the likelihood of recurrence in future pregnancies. This information also helps families prepare emotionally and financially for potential medical needs after birth.

Choosing Between Basic and Extended NIPT

While extended NIPT offers a broader scope of screening, it also comes with additional considerations:

1. Cost: Extended NIPT is typically more expensive than basic NIPT, which may influence accessibility.
2. Time-Consuming: Because of the complexity of the tests, some of the extended NIPTs can have much longer turnaround time.
3. False Positives: Screening for microdeletions and sex chromosome aneuploidies may yield higher rates of false positives compared to basic NIPT, necessitating confirmatory diagnostic tests such as amniocentesis or chorionic villus sampling (CVS). Among the various conditions tested, extended NIPT shows the poorest performance for these two categories due to different biological and technical challenges.
4. False-Negatives: All NIPTs are screening tests and can have false-negative results due to technological limitations and biological reasons. Many genetic conditions are associated with multiple genes, and these tests are designed to detect only known and relatively common pathogenic mutations, leaving rarer or unknown variants undetected.
5. There is a small possibility of identifying a pathogenic single-gene variant (mutation) inherited from a parent. For example, a parent may carry a mild or subclinical form of a genetic disorder without being aware of it. Thorough genetic counselling is essential in such cases to evaluate the potential impact of this variant on the unborn child and to provide tailored advice for the family.
6. Counselling Needs: The complexity of results from extended NIPT often requires detailed genetic counselling to help families understand the findings and their implications.
7. Only highly advanced genomic laboratories can develop extended NIPT tests capable of detecting monogenic conditions and microdeletions. While these branded extended NIPTs are extensively evaluated and validated internally, they still lack independent validation. It is essential to mention that even basic NIPTs, such as the widely used TDL NIPT in London, have not been validated by external organisations, leaving the actual performance of these tests uncertain.

Genetic Labs and Their Brands of Extended NIPT

Fulgent Genetics (US), an accredited leader in clinical diagnostic genetic sequencing, provides the KNOVA test, which screens for a wide range of single-gene disorders and chromosomal anomalies. KNOVA features a meticulously curated panel of de novo genetic conditions designed to optimise diagnostic performance while minimising false-positive rates. Currently, KNOVA is regarded as one of the best choices for extended NIPT panels in the UK. At London Pregnancy Clinic we offer it as part of out state-of-the-art SMART Test NIPT screening method.

Natera’s (US) Panorama test, which includes screening for microdeletions, and the separate Vistara test, focuses on single-gene disorders. Natera was a pioneer in the development of extended NIPT; however, other companies now offer more comprehensive screening panels. Notably, the Panorama test for 22q11.2 deletion syndrome is the only extended NIPT validated by an independent study, demonstrating a detection rate of approximately 80% and a positive predictive value of about 50%.

Eurofins Genoma (Italy) offers the PrenatalSafe Complete Plus test, which screens for all aneuploidies, microdeletions, and selected monogenic disorders. A unique feature of this test is its ability to screen for cystic fibrosis and its applicability in cases of vanishing twin syndrome. However, PrenatalSafe Complete Plus has a limited monogenic disorders panel, a very long turnaround time, and is relatively expensive.

BGI Genomics (China) features the NIFTY Mono test, specialising in detecting monogenic conditions and other genetic anomalies. Nifty Mono offers probably the most comprehensive panel, screening for hundreds of chromosomal and genetic disorders. However, there are significant concerns regarding the use of patient data by BGI. In 2023, a group of MPs and peers in the UK submitted a letter to the Information Commissioner’s Office, requesting an investigation into privacy concerns surrounding BGI Group, particularly its NIFTY prenatal tests.

BillionToOne (US) offers the UNITY test, which uniquely combines carrier screening with fetal screening. UNITY screens for inherited single-gene disorders such as cystic fibrosis, sickle cell anaemia, and thalassemias, providing detailed insights into both parental and fetal genetic health. Notably, the UNITY and KNOVA panels are complementary, enabling enhanced diagnostic performance when used together. 

Final Thoughts.

Choosing between basic and extended NIPT depends on individual circumstances, risk factors, and the level of detail desired in genetic screening. While basic NIPT provides robust detection of common aneuploidies, extended NIPT offers a deeper dive into genetic health by screening for microdeletions and single-gene disorders. It is anticipated that future developments in extended NIPT panels will increasingly focus on screening for monogenic (single-gene) disorders, given their clinical significance and the growing demand for more comprehensive prenatal testing options. Consulting with healthcare professionals and genetic counsellors can help families navigate these choices and ensure the best possible care for both the expectant mother and her baby.

When choosing a clinic for your NIPT, ensure they use advanced high-resolution ultrasound technology for the pre-test scan. High-quality imaging allows for a more accurate assessment of fetal health, which is crucial, particularly in the early stages of pregnancy (10-11 weeks). Avoid clinics with outdated or low-resolution scanners, as this can compromise the accuracy of the scan and potentially impact the performance of your NIPT.