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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

If you are considering SNP-based NIPTs for your patients, PanoramaTM by Natera is a good place to start; it is rigorously validated and accurate.


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

To discover whether Panorama, a SNP-based NIPT developed by Natera, is a good choice for your practice, visit our Panorama page here.



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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.

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