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How SNP-Based NIPTs Enable Better Detection of 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome, which occurs when a portion of chromosome 22 is missing, is the most common deletion in humans.1,2 The size of the missing piece varies significantly, as does the clinical presentation of the syndrome.3 The variability in symptoms results in the syndrome often going unrecognized for years, with many people not diagnosed until late childhood.

The prevalence of 22q11.2 deletions is comparable to that of regularly screened for aneuploidies

While 22q11.2 deletion syndrome was once thought to occur in 1 out of 4,000 births, it is now recognized that the syndrome has likely long been underdiagnosed. Today it is assumed that 22q11.2 deletion syndrome occurs at least twice as often, or 1 in 2,000, making it comparable in frequency to some of the aneuploidies for which OBs regularly screen.4,5 Because common aneuploidies, such as trisomies 21, 18, and 13, are associated with maternal age and 22q11.2 deletion syndrome is not, 22q11.2 deletion syndrome occurs at comparable rates to the most common aneuploidy, trisomy 21, in children of younger mothers.6

22q11.2 deletion is also more common than both cystic fibrosis and spinal muscular atrophy, which are part of standard, panethnic carrier screening.

Early diagnosis of 22q11.2 deletion syndrome improves outcomes

Although early diagnosis of 22q11.2 deletion syndrome – especially prenatally or neonatally – can improve health outcomes, most children are not diagnosed until an average age of 4, especially if no cardiac defects are present.3,7 Thus, most patients with 22q11.2 deletion syndrome do not receive early interventions to treat problems associated with 22q11.2 deletion syndrome during critical developmental periods. These include:8,9

  • Hypocalcemia. If untreated, the hypocalcemia that occurs with 22q11.2 deletion syndrome can lead to severe neurodevelopmental deficits.
  • Immune deficiencies. The immune deficiencies that can occur with 22q11.2 deletion syndrome can lead to avoidable infections, especially in children undergoing surgeries.
  • Palatal abnormalities. While some palatal abnormalities that occur with 22q11.2 deletion syndrome are obvious, such as cleft palate, others can go undetected and lead to feeding difficulties and failure to thrive.
  • Congenital heart defects. Important interventions for congenital heart defects can be delayed when these defects go undetected because of a lack of 22q11.2 deletion syndrome diagnosis. Unfortunately, even standard critical congenital heart disease (CCHD) screens often miss relevant defects, compounding the importance of early detection of 22q11.2 deletion syndrome to mitigate cardiovascular risks.

Obviously, earlier diagnosis allows clinical care to be adjusted accordingly. For example, pregnant mothers can be advised to deliver their babies at tertiary care centers to ensure that specialists are available to immediately provide needed interventions. In addition, sonographers can evaluate for evidence of cardiac and palatal defects, at birth, calcium levels can be monitored and administration of live vaccines can be delayed.10

Traditional screens cannot detect many 22q11.2 deletions

Screening for 22q11.2 deletions is critical, given the prevalence of 22q11.2 deletion syndrome and the clinical benefits of early diagnosis. However, conventional screening techniques like counting-based NIPTs - which are not SNP-based and ultrasound - are limited in their ability to identify 22q11.2 deletion syndrome. Contributing to these limitations are the inability for counting-based NIPTs to differentiate maternal from fetal DNA and the non-specificity of ultrasound. While little published data exists regarding the clinical validation of counting-based NIPTs in screening for 22q11.2 deletions, studies have demonstrated that these NIPTs have a low sensitivity for identifying these deletions because of their small size.11 One relevant study found that counting-based NIPTs can only identify deletions of 7 megabase pairs, at a rate of approximately 20% with a fetal fraction of 10%.12 The size of the most common 22q11.2 microdeletion is less than half of 7 megabases, suggesting that non-SNP-based NIPTs would not reliably identify these deletions.

SNP-based NIPTs have an unmatched ability to detect 22q11.2 deletions

SNP-based NIPTs overcome the challenges associated with identifying 22q11.2 deletions, including small, nested deletions, which have traditionally been considered to represent about 15% of all 22q11.2 deletion syndrome cases. This ability of SNP-based NIPTs to find and characterize these small deletions has revealed that these deletions likely occur more frequently than we knew, before we could directly identify them. Analytical and clinical validation data on SNP-based NIPTs has demonstrated a high sensitivity and specificity for 22q11.2 deletion syndrome. 2,13–20 This data suggests SNP-based NIPTs are best for accurately screening for 22q11.2 deletions.

Now, the algorithm powering SNP-based NIPT platform also utilizes artificial intelligence (AI) to improve both the specificity and sensitivity for identifying 22q11.2 deletions. This improvement enables SNP-based NIPTs to detect microdeletions that are 10 times smaller than those that can be detected by most other counting-based NIPTs.2,12 The SNP-based Microdeletion and Aneuploidy RegisTry (SMART) study involved more than 20,000 patients across 21 sites across the world. SMART showed that the latest version of SNP-based NIPT enhances the sensitivity for full deletions to greater than 99.9%, and to 83% for all deletions down to 0.5 megabase pairs.2 Moreover, the improved specificity of SNP-based NIPT demonstrated a positive predictive value of 53%.2

Takeaway

Improving our ability to diagnose 22q11.2 deletion syndrome earlier has clear benefits for babies by treatment from birth. Prenatally, it has been challenging to diagnose 22q11.2 deletion syndrome prenatally with traditional screening methods like counting-based NIPT because these methods are limited in their technical capacity to identify the small deletions associated with 22q11.2 deletion syndrome. SNP-based NIPTs have high sensitivity and specificity for identifying deletions of all sizes, and thus provide a new opportunity to reliably diagnose 22q11.2 deletion syndrome earlier than ever, and to provide the earliest newborn treatment.

Get resources on 22q11.2 deletion syndrome here and learn more about the SMART study here

 

References

1Sgardioli IC, Paoli Monteiro F, Fanti P, Paiva Vieira T, Gil-da-Silva-Lopes VL. Testing criteria for 22q11.2 deletion syndrome: preliminary results of a low cost strategy for public health. Orphanet Journal of Rare Diseases 2019 14:1. 2019;14(1):1-8. doi:10.1186/S13023-019-1098-1

2Dar et al. Multicenter prospective study of SNP-based cfDNAscreening for aneuploidy with genetic confirmation in 18,497 pregnancies. In: Society of Maternal-Fetal Medicine (SMFM). ; 2021.

3McDonald-McGinn DM, Sullivan KE, Marino B, et al. 22q11.2 deletion syndrome. Nature Reviews Disease Primers 2015 1:1. 2015;1(1):1-19. doi:10.1038/nrdp.2015.71

4Risks of Trisomy 21, 18, 13 (Snijdres et al, Ultrasound Obst Gynecol - 1999; 13: 167-70). Accessed September 15, 2021. https://sonoworld.com/Client/Fetus/html/appendix-01/appendix-01.html

5Gross SJ, Bajaj K, Garry D, et al. Rapid and novel prenatal molecular assay for detecting aneuploidies and microdeletion syndromes. Prenatal Diagnosis. 2011;31(3):259-266. doi:10.1002/PD.2674

6Snijders RJM, Sundberg K, Holzgreve W, Henry G, Nicolaides KH. Maternal age- and gestation-specific risk for trisomy 21. Ultrasound in Obstetrics and Gynecology. 1999;13(3):167-170. doi:10.1046/J.1469-0705.1999.13030167.X

7LD P, NJ B, E B, et al. Elucidating the diagnostic odyssey of 22q11.2 deletion syndrome. American Journal of Medical genetics Part A. 2018;176(4):936-944. doi:10.1002/AJMG.A.38645

8McDonald-McGinn DM, Hain HS, Emanuel BS, Zackai EH. 22q11.2 Deletion Syndrome. Obstetric Imaging: Fetal Diagnosis and Care, 2nd Edition. Published online February 27, 2020:621-626.e1. Accessed September 15, 2021. https://www.ncbi.nlm.nih.gov/books/NBK1523/

9Cheung ENM, George SR, Andrade DM, Chow EWC, Silversides CK, Bassett AS. Neonatal hypocalcemia, neonatal seizures, and intellectual disability in 22q11.2 deletion syndrome. Genetics in Medicine 2014 16:1. 2013;16(1):40-44. doi:10.1038/gim.2013.71

10AS B, DM M-M, K D, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. The Journal of Pediatrics. 2011;159(2):332-9.e1. doi:10.1016/J.JPEDS.2011.02.039

11LM L, CS S, KC C, SWS S, P B. Screening for 22q11.2 deletion syndrome by two non-invasive prenatal testing methodologies: A case with discordant results. Taiwanese journal of obstetrics & gynecology. 2019;58(1):40-42. doi:10.1016/J.TJOG.2018.11.006

12Zhao C, Tynan J, Ehrich M, et al. Detection of Fetal Subchromosomal Abnormalities by Sequencing Circulating Cell-Free DNA from Maternal Plasma. Clinical Chemistry. 2015;61(4):608-616. doi:10.1373/CLINCHEM.2014.233312

13Analytical Validation of the Verifiprenatal Test.; 2012.

14Ryan A, Hunkapiller N, Banjevic M, et al. Validation of an Enhanced Version of a Single-Nucleotide Polymorphism-Based Noninvasive Prenatal Test for Detection of Fetal Aneuploidies. Fetal Diagnosis and Therapy. 2016;40(3). doi:10.1159/000442931

15Nicolaides KH, Syngelaki A, Gil MDM, Quezada MS, Zinevich Y. Prenatal detection of fetal triploidy from cell-free DNA testing in maternal blood. Fetal Diagnosis and Therapy. 2014;35(3):212-217. doi:10.1159/000355655

16Nicolaides KH, Syngelaki A, Gil M, Atanasova V, Markova D. Validation of targeted sequencing of single-nucleotide polymorphisms for non-invasive prenatal detection of aneuploidy of chromosomes 13, 18, 21, X, and Y. Prenatal Diagnosis. 2013;33(6):575-579. doi:10.1002/PD.4103

17Bianchi D, Platt L, Goldberg J, et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstetrics and Gynecology Publications. 2012;119(5):890-901. doi:10.1097/AOG.0b013e31824fb482

18Bianchi DW, Parker RL, Wentworth J, et al. DNA Sequencing versus Standard Prenatal Aneuploidy Screening. http://dx.doi.org/101056/NEJMoa1311037. 2014;370(9):799-808. doi:10.1056/NEJMOA1311037

19Ravi H, McNeill G, Goel S, et al. Validation of a SNP-based non-invasive prenatal test to detect the fetal 22q11.2 deletion in maternal plasma samples. PLOS ONE. 2018;13(2):e0193476. doi:10.1371/JOURNAL.PONE.0193476

20Dugoff L, Mennuti MT, McDonald-McGinn DM. The benefits and limitations of cell-free DNA screening for 22q11.2 deletion syndrome. Prenatal Diagnosis. 2017;37(1):53-60. doi:10.1002/PD.4864

 

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