Mid- and late pregnancy

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Genetic Testing Advance Refines Prenatal Anomaly Detection

WASHINGTON – A refined application of single nucleotide polymorphism (SNP) array technology is bolstering the accuracy of prenatal genetic testing, offering earlier adn more precise insights into potential fetal abnormalities, according to a new study. This advancement is especially significant in cases flagged by non-invasive prenatal testing (NIPT), where anomalies on chromosomes known for imprinting disorders are suspected.

SNP arrays, regarded as the “gold standard,” excel at identifying regions of homozygosity (ROH), which can reveal conditions such as uniparental disomy (UPD), ancestral homozygosity, and consanguinity. ROH occurs when an individual inherits two identical copies of a chromosome or a portion of a chromosome from one parent, rather of one copy from each parent.

Now, U.S. scientists are expanding on global research to understand the complex interplay between ROH,UPD,and potential developmental issues,reinforcing the need for comprehensive genetic screening protocols.

ROH Detection Rates Vary

The original study examined 6,176 fetal samples subjected to SNP array analysis over six years. The detection rate of ROH was 1.41% (87/6176), which researchers noted was “significantly higher” than rates reported at other centers.This variation, experts believe, is likely linked to sample selection.

“In our study, the proportion of invasive diagnoses due to positive NIPT results was as high as 27.1% (1674/6176), with the highest positive rate for ROH (2.03%) among all indications,” researchers stated. NIPT relies on cell-free fetal DNA found in the mother’s blood, which primarily reflects placental chromosomal conditions.

Scientists confirmed that in cases with normal copy numbers, 85.3% (29/34) of ROH cases aligned with positive NIPT results. “In cases of aberrant NIPT, especially on chromosomes with clinically significant imprinting disorders on chromosomes 6, 7, 11, 14, 15, and 20, prenatal diagnostic techniques that recognize ROH or UPD, such as SNP array, should be prioritized,” the team emphasized.

Recent data from the National institutes of Health (NIH) highlights the increasing use of NIPT in the U.S., with a corresponding rise in follow-up testing to confirm or clarify NIPT results. This trend underscores the importance of accurate and comprehensive diagnostic tools like SNP arrays.UPD: When Chromosome Correction Goes Awry

UPD arises when an initial chromosomal imbalance corrects itself, leading to a normal chromosome number but with both copies originating from a single parent. This can manifest as heterodisomy (two different chromosomes from one parent), isodisomy (two identical copies from one parent), or a combination of both.

The primary mechanisms behind this self-correction include trisomy rescue, monosomy rescue, and gamete complementation. Roughly “19% of the reported UPD cases are due to trisomic rescue,” while isodisomy is often linked to monosomy rescue. However,”incomplete self-correction results in a cytogenetic abnormality in UPD,” with about 35% of UPD cases presenting with an abnormal karyotype.

Recent studies published in the American Journal of Human Genetics have explored the long-term health outcomes of individuals with UPD, revealing a spectrum of potential developmental and health challenges, depending on the chromosome involved and the specific type of disomy.

UPD detection Rates and Clinical Significance

The study identified 15 cases of UPD from 6176 pregnancies, yielding a detection rate of 0.24%, which is “significantly higher than the general population frequency of 0.05%.”

“The detection rate of UPD in the prenatal period would be much higher than this incidence becuase more than one-third of UPDs cannot be detected by CMA,” the study noted. This limitation emphasizes the need for advanced techniques, like SNP arrays, to identify these subtle genetic variations.

The medical consequences of UPD range from autosomal recessive diseases (in cases of isodisomy) to imprinting disorders.Specific syndromes associated with UPD include Prader-Willi syndrome, Angelman syndrome, and Beckwith-Wiedemann syndrome. These syndromes frequently enough involve disordered growth or development,particularly prenatal growth.Fetal growth restriction (FGR) was the most common ultrasound symptom observed in the study. These findings emphasize the necessity of differentiating FGR caused by confined placental mosaicism (CPM) from imprinting disorders. experts advocate for “the combination of genetic counseling, karyotyping, WES, CMA, NIPT, placental studies, and prenatal ultrasonography” to provide robust identification and management of UPD, specifically those linked to FGR.Counterpoint: the Risk of Over-Interpretation

While the increased sensitivity of SNP arrays offers improved detection, some experts caution against over-interpreting ROH findings. Detecting ROH “by itself is not diagnostic of any underlying condition and may be clinically benign.” The clinical relevance should be carefully assessed by first determining if ROH occurs alongside an abnormal karyotype. Next, it is significant to distinguish between excessive homozygosity in multiple regions and restricted ROH, experts say. The study found that for “total homozygous regions less than 180 Mb,” the risk of autosomal recessive disorders is similar to the general non-consanguineous population.

The Path Forward

The integration of SNP array technology into prenatal diagnostic protocols represents a significant step forward in identifying and understanding fetal genetic anomalies. While challenges remain in interpreting the clinical significance of certain findings, ongoing research and refined guidelines promise to enhance the accuracy and utility of these powerful diagnostic tools.

FAQ: Understanding ROH and UPD

What is a SNP array?
A SNP array is a type of genetic test that analyzes single nucleotide polymorphisms (SNPs) across a person’s genome. SNPs are variations in a single nucleotide (A, T, C, or G) within a DNA sequence. SNP arrays can detect regions of homozygosity (ROH), uniparental disomy (UPD), and other genetic abnormalities.
What are regions of homozygosity (ROH)?
ROH are segments of DNA where a person has inherited identical copies of a chromosome or part of a chromosome from one parent. ROH can indicate consanguinity, ancestral homozygosity, or uniparental disomy.
What is uniparental disomy (UPD)?
UPD occurs when a person inherits two copies of a chromosome from one parent and no copy from the other parent. This can lead to genetic disorders, especially if the chromosome contains imprinted genes.
What Should Expectant Parents Do?
If NIPT results suggest the possibility of ROH or UPD, consult with a genetic counselor to understand the implications and explore further diagnostic testing options, such as SNP array analysis. These tests delve more deeply into your baby’s genetic makeup, providing more information for your medical team.
* Are there any ethical considerations when using SNP arrays in prenatal testing?
Yes, genetic testing can reveal unexpected information about the parents or the fetus, leading to difficult decisions. Genetic counseling is essential to help families understand the potential outcomes and make informed choices.

What are the limitations of SNP arrays in detecting genetic variants?

Interview: Prenatal Genetic Testing and SNP Arrays with Dr. Elara Vance

Welcome back to Archyde! Today, we have the pleasure of speaking with Dr. Elara Vance, a leading geneticist specializing in prenatal diagnostics. Dr. Vance, thank you for joining us.

Dr. Vance: It’s my pleasure to be here. Thank you for having me.

The Role of SNP Arrays in Prenatal Screening

Archyde: Let’s dive right in. Our recent report highlighted advancements in prenatal genetic testing using SNP array technology.For our readers, could you briefly explain what a SNP array is and what it does?

Dr. Vance: Certainly. A SNP array, or single nucleotide polymorphism array, analyzes the entire genome for variations. It identifies regions of homozygosity (ROH) and uniparental disomy (UPD), which are critically important indicators of potential genetic issues in a fetus. They are often the “gold standard” for confirmatory testing following abnormal NIPT results.

Archyde: That’s a good overview. According to recent studies featured in our report, there’s a growing emphasis on the role of these arrays, especially in cases initially flagged by non-invasive prenatal testing or NIPT, isn’t there?

Dr.Vance: Absolutely. NIPT is a valuable screening tool, but it has limitations. When NIPT suggests an issue, especially on chromosomes involved with imprinting disorders or indicates ROH or UPD, SNP arrays can provide more detailed and precise information, helping to guide further management of the pregnancy or diagnostic testing.

Understanding ROH and UPD: A Deeper Look

Archyde: Can you elaborate on the key differences between ROH and UPD and,when they are identified,why is that concerning?

Dr. vance: ROH, as mentioned, is when a child inherits the same genetic material from both parents in a particular region. UPD means the child inherits both copies of a chromosome from just one parent. Both can perhaps lead to problems. ROH heightens the chance of finding harmful recessive genes.UPD, particularly when it involves chromosomes with imprinted genes, can cause developmental disorders because these genes often behave differently depending on which parent they come from.

Archyde: The study showed a detection rate of 0.24% for UPD, which may be higher than the general population. What are the limitations of SNP arrays in detecting genetic variants?

Dr. Vance: While SNP arrays are powerful,they are generally not considered a first line diagnostic tool for all prenatal conditions.they cannot detect smaller genetic changes,such as single gene mutations. So, in the context of a prenatal screening, the SNP array confirms indications from a NIPT screening, and it should be followed by genetic counseling, karyotyping, or other in-depth examinations. The results are very dependent on the quality of genetic testing labs and their ability to assess a high volume of samples efficiently.

Interpreting results and Clinical Significance

Archyde: The study mentions the risk of over-interpreting ROH findings. How should clinicians approach the clinical significance of ROH?

Dr. Vance: That’s a very critically important point. ROH alone isn’t automatically a diagnosis.We must consider the context. Is there an abnormal karyotype? Is it a widespread finding of ROH, or is it limited? We might be looking at an increased risk of autosomal recessive disorders, especially with extensive homozygosity from two parents that are related.

Archyde: What advice would you give to expectant parents who receive concerning NIPT results, potentially indicating ROH or UPD?

Dr. Vance: First, don’t panic. It’s crucial to consult a genetic counselor and seek additional diagnostic testing, potentially including SNP array analysis. genetic counseling can help clarify the chances of an adverse outcome, discuss the implication, and help parents make informed decisions about the best course of action.

Archyde: are there any ethical considerations related to the use of SNP arrays in prenatal testing?

Dr. Vance: Absolutely.These tests can uncover unexpected information, which can be arduous for families. Genetic counseling must be a key part of this process to help families understand the results and make decisions consistent with what they can reasonably manage.

The Future of Prenatal Genetic Testing

Archyde: Looking ahead, what advancements do you foresee in prenatal genetic testing?

Dr. Vance: Currently, we’re seeing improvements in the interpretation of ROH and UPD findings. Combining data from a variety of sources,like NIPT,SNP arrays,and other tests from genetic labs,delivers a very accurate picture. We’re getting closer to better personalized management. Greater standardization of interpretation and more access to advanced genetic testing is in our future as well.

Archyde: That’s great to hear. what is one question you wish everyone understood when they read about this topic?

Dr. Vance: I want people to understand the importance of consulting experts in the field. Genetics can be elaborate, and interpretation relies on a extensive outlook, making an initial consult with a genetic counselor helpful.

Archyde: Dr. Vance, thank you so much for this valuable insight. It’s been highly informative.

Dr. Vance: Thank you for having me.

Archyde: and thank you, our readers, for tuning in. We encourage you to share your thoughts or questions in the comments below. We’d love to hear from you!