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Occurrence and importance of testing for microdeletion syndromes​

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Microdeletions are a topic of extensive genetic research. These small deletions in the DNA sequence of a chromosome can have significant implications on an individual’s health. In this comprehensive blog post, we delve into the causes, risk factors, ten most common types of microdeletions, their prevalence, and the role of Non-Invasive Prenatal Testing (NIPT) in their detection.

What are Microdeletions?

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Microdeletions are tiny losses of genetic material in the DNA sequence of a chromosome. These minute changes are typically undetectable under a standard microscope, hence the term ‘micro’. However, despite being minute, these deletions can lead to significant health and developmental problems, as they may disrupt several genes essential for growth and development.

 

Causes and Risk Factors

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The exact cause of microdeletions remains unknown, and their occurrence seems largely spontaneous. They typically occur during the formation of reproductive cells or in early foetal development, resulting from a mistake in the cell’s DNA replication process.

In terms of risk factors, there’s no established link between microdeletions and parental age, ethnicity, or lifestyle. These changes can happen in any pregnancy, but familial history can increase the chances if a parent has a balanced translocation or an inherited microdeletion.

 

The Ten Most Common Microdeletion Syndromes

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Here’s a list of ten of the most common microdeletion syndromes, along with their estimated prevalence:

 

Syndrome                                                                                                         Approximate Prevalence

1. DiGeorge Syndrome (22q11.2 deletion syndrome)                              1 in 3,000 – 1 in 6,000

2. Williams Syndrome (7q11.23 deletion syndrome)                                1 in 7,500 – 1 in 20,000

3. Prader-Willi Syndrome                                                                              1 in 10,000 – 1 in 25,000

4. Angelman Syndrome                                                                                 1 in 10,000 – 1 in 20,000

5. Cri-du-chat Syndrome (5p- syndrome)                                                   1 in 20,000 – 1 in 50,000

6. 1p36 Deletion Syndrome                                                                          1 in 5,000 – 1 in 10,000

7. Wolf-Hirschhorn Syndrome (4p- syndrome)                                         1 in 20,000 – 1 in 50,000

8. Smith-Magenis Syndrome (17p11.2 deletion syndrome)                    1 in 15,000 – 1 in 25,000

9. Alagille Syndrome (20p12 deletion syndrome)                                     1 in 30,000 – 1 in 50,000

10. Rubinstein-Taybi Syndrome                                                                   1 in 100,000 – 1 in 125,000

 

Microdeletions, in general, occur in approximately 1 in every 1,000 births, making them a significant contributor to genetic disorders. Just to compare Down’s Syndrome, the most common chromosomal disorder affects approximately 1 in 1,000 to 1 in 1,100 live births worldwide. The frequency of Down’s Syndrome increases significantly with the mother’s age, particularly from 35 years onwards whereas microdeletions are believed to occur randomly.

 

Microdeletion Screening: The Role of NIPT

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Screening for microdeletions has been revolutionised by advancements in genetic testing, particularly with the introduction of Non-Invasive Prenatal Testing (NIPT). This screening test, typically performed from the 10th week of pregnancy, analyses cell-free DNA in the maternal blood to identify common chromosomal abnormalities and microdeletions. NIPT poses no risk to the foetus and offers a safer alternative to invasive diagnostic procedures.

Though NIPT has high accuracy rates, it’s crucial to understand that a ‘positive’ result indicates an increased risk, not a definitive diagnosis. Positive NIPT results should always be confirmed through diagnostic tests such as amniocentesis or chorionic villus sampling (CVS).

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Conclusion

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While the world of microdeletions might seem complex, understanding them is crucial to advancing our knowledge of genetic disorders. Early detection, made possible by advanced screening methods like NIPT, allows for better preparation and potential intervention. As research continues to evolve, we can hope for even more effective detection and management of these genetic changes, ultimately leading to improved healthcare and patient outcomes.

Fetal fraction, why it matters

 

Why Fetal Fraction is an important parameter within your NIPT Results

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Expecting a baby is an exciting time, filled with anticipation and, let's be honest, a few worries. Non-invasive prenatal testing (NIPT) has become a popular option for many parents-to-be, offering early insights into the baby's genetic health with just a simple blood draw. But while you might hear a lot about "high-risk" or "low-risk" results, there's a lesser-known, yet incredibly vital, factor at play: fetal fraction (FF).

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Here at Prenata, and indeed worldwide, understanding fetal fraction is an important parameter in making sense of your NIPT. It’s not just a random number; it's the cornerstone of the test's accuracy.

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What Exactly is Fetal Fraction?

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Think of your blood as a river carrying tiny genetic messages. During pregnancy, your blood contains DNA from both you and your baby (specifically, from the placenta, which is genetically identical to your baby). Fetal fraction is simply the percentage of your baby's DNA found within the total cell-free DNA (cfDNA) fraction circulating in your blood.

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So, if your NIPT report says your fetal fraction is 8%, it means 8% of the DNA being analyzed in that blood sample belongs to the fetus.

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Why Does This Percentage Matter So Much?

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The brilliance of NIPT lies in its ability to detect very subtle differences in the amount of DNA from specific chromosomes, which can indicate conditions like Down syndrome (Trisomy 21). But to spot these tiny variations, the test needs enough "signal" from the baby.

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Here's why it's so critical:

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  • Accuracy is King: A higher fetal fraction generally translates to a more accurate and reliable NIPT result. With more of your baby's DNA to analyze, the statistical confidence in identifying or ruling out a chromosomal condition significantly increases. Research has repeatedly demonstrated that FF is a crucial parameter affecting the accuracy of NIPT [1].

  • Avoiding "No-Call" Results: Most NIPT labs require a minimum fetal fraction, often between 2-4%. If the FF falls below this threshold, the lab won't have enough fetal DNA to make a confident call. This leads to a "no-call" result, which has been reported to occur in 1% to 8% of pregnancies, depending on the lab and technology used [2].

  • Guiding Next Steps: A low fetal fraction isn't just an inconvenience; it can be an important piece of information. Sometimes, it just means you need to wait a few more weeks for a re-test, as FF naturally increases with gestational age. Other times, a persistently low FF can subtly increase concerns and might lead your healthcare provider to discuss more invasive diagnostic tests like amniocentesis or CVS, especially if there are other clinical indications [3].

  • Early Warning System: While rare, a low FF has been associated with a higher risk of certain aneuploidies, particularly Trisomy 13 and 18 [4]. Conversely, an unusually increased FF has been linked to potential adverse pregnancy outcomes, such as spontaneous preterm birth or an abnormally invasive placenta [5].

 

What Influences Fetal Fraction?

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Several factors can impact your fetal fraction:

  • Gestational Age: This is the biggest one! As your pregnancy progresses, the amount of fetal DNA in your blood naturally increases. This is why NIPT is typically recommended after 10 weeks of pregnancy, and studies show a strong positive correlation between FF and gestational age [6].

  • Maternal Weight: There's an inverse relationship here. People with a higher Body Mass Index (BMI) often have a lower fetal fraction. This is likely because a larger maternal blood volume dilutes the fetal DNA present, a finding consistently supported by research [7].

  • Fetal Chromosomal Conditions: In some cases, certain fetal aneuploidies (like Trisomy 13 or 18) can be associated with a slightly lower fetal fraction [8].

 

The Takeaway for Clinicians and Patients

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When you receive your NIPT results, don't just focus on the "high" or "low" risk categories. Take a moment to understand the fetal fraction mentioned in your report. It's a key indicator of how robust and reliable your results are.

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If you get a "no-call" due to low fetal fraction, try not to panic. It's often just a matter of waiting a couple of weeks for a re-draw. Your healthcare provider will be able to explain your specific results and guide you through any necessary next steps including a re-draw of blood and re-test a few weeks later if required.

 

Publication References:

  1. Deng, C., & Liu, S. (2022). Factors Affecting the Fetal Fraction in Noninvasive Prenatal Screening: A Review. Frontiers in Pediatrics, 10, 812781. https://www.researchgate.net/publication/358184871_Factors_Affecting_the_Fetal_Fraction_in_Noninvasive_Prenatal_Screening_A_Review

  2. Scott, F., et al. (2016). The implications of non-invasive prenatal testing failures: A review of an under-discussed phenomenon. Prenatal Diagnosis, 36(9), 834-840. https://www.researchgate.net/publication/297585086_The_implications_of_non-invasive_prenatal_testing_failures_A_review_of_an_under-discussed_phenomenon

  3. Pergament, E., et al. (2014). Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk pregnancy population. Obstetrics & Gynecology, 124(2 Pt 1), 226-231. https://pubmed.ncbi.nlm.nih.gov/25000508/

  4. Wang, E., et al. (2013). The impact of fetal fraction on the performance of a targeted massively parallel sequencing-based noninvasive prenatal test. Prenatal Diagnosis, 33(7), 639-646. https://pubmed.ncbi.nlm.nih.gov/23729352/

  5. Wang, E., et al. (2016). Fetal fraction and maternal body mass index in non-invasive prenatal testing: The clinical implications of an unusually high fetal fraction. Prenatal Diagnosis, 36(6), 569-574. https://pubmed.ncbi.nlm.nih.gov/27184288/

  6. Ashoor, G., et al. (2013). Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks' gestation: relation to maternal and fetal characteristics. Ultrasound in Obstetrics & Gynecology, 41(1), 21-26. https://obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/uog.11211

  7. Bianchi, D. W., et al. (2014). Maternal and fetal factors that affect the fetal fraction in noninvasive prenatal testing. Journal of Perinatology, 34(2), 112-117. https://www.nature.com/articles/jp2013144

  8. Lau, C. H. Y., et al. (2014). Fetal fraction in non-invasive prenatal testing for trisomy 21: a systematic review. Prenatal Diagnosis, 34(10), 917-926. https://obgyn.onlinelibrary.wiley.com/doi/full/10.1002/pd.4452

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