Noninvasive cell-free DNA prenatal screening may accurately detect velocardiofacial syndrome
Prenatal screening for genetic disorders has traditionally focused on screening for Down syndrome (T21) and other aneuploidies (T13 and T18) in the fetus. However, such chromosomal aneuploidies constitute a relatively small proportion of the total number of genetic conditions that contribute to adverse infant and childhood outcomes. In recent years, noninvasive prenatal screening based on sequencing of circulating cellfree DNA (cfDNA) in maternal blood has introduced the potential to target any region of the genome, including an option to screen for subchromosomal copy number variants such as chromosomal microdeletions.
Although individually rare, in aggregate, chromosomal microdeletions and duplications are more prevalent than the common trisomies, and because their birth incidence is not associated with increasing maternal age, they are more common than T21 in women <30 years of age. The most common of these is the 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge or velocardiofacial syndrome. This condition is characterized by variable features including congenital heart defects and developmental delay in most patients, a cleft palate or velopharyngeal insufficiency, hypocalcemia, immunodeficiency, autism, and psychiatric disorders. The 22q11.2DS has been estimated to affect approximately 1 in 3000 to 6000 live births and is therefore one of the most common causes of developmental delay and congenital heart anomalies. These mostly de novo deletions are caused by meiotic recombination events in 4 hot spot regions known as A-D low-copy repeats (LCR) on the long arm of chromosome 22.
In addition to providing parents with important information about their pregnancy, antenatal diagnosis of 22q11.2DS has the potential to improve short- and long-term outcomes for these children.
Dar P et al sought to assess the performance of single-nucleotide polymorphism (SNP) ebased cfDNA screening for 22q11.2DS in a large prospective study with genetic confirmation in all pregnancies.
Patients who underwent single-nucleotide polymorphism based prenatal cell-free DNA screening for 22q11.2 deletion syndrome were prospectively enrolled at 21 centers in 6 countries. Prenatal or newborn DNA samples were requested in all cases for genetic confirmation using chromosomal microarrays. The primary outcome was sensitivity, specificity, positive predictive value, and negative predictive value of cell-free DNA screening for the detection of all deletions, including the classical deletion and nested deletions that are 500 kb, in the 22q11.2 low-copy repeat A-D region. Secondary outcomes included the prevalence of 22q11.2 deletion syndrome and performance of an updated cell-free DNA algorithm that was evaluated with blinding to the pregnancy outcome.
Of the 20,887 women enrolled, a genetic outcome was available for 18,289 (87.6%). A total of 12 22q11.2 deletion syndrome cases were confirmed in the cohort, including 5 (41.7%) nested deletions, yielding a prevalence of 1 in 1524.
In the total cohort, cell-free DNA screening identified 17,976 (98.3%) cases as low risk for 22q11.2 deletion syndrome and 38 (0.2%) cases as high risk; 275 (1.5%) cases were nonreportable.
Overall, 9 of 12 cases of 22q11.2 were detected, yielding a sensitivity of 75.0%; specificity of 99.84%; positive predictive value of 23.7% and negative predictive value of 99.98%. None of the cases with a nonreportable result was diagnosed with 22q11.2 deletion syndrome.
The updated algorithm detected 10 of 12 cases (83.3%) with a lower false positive rate (0.05% vs 0.16%; P<.001) and a positive predictive value of 52.6% (10/19).
In this multicenter prospective study, authors found that prenatal screening for 22q11.22DS with SNP-based cfDNA has high sensitivity and specificity in a diverse, real-world population. These findings demonstrate that routine noninvasive prenatal screening using cfDNA for genetic disorders beyond aneuploidy is possible with high accuracy.
Given the increasing use of cfDNA as a primary screening tool for common aneuploidies, clinical significance and test performance are important when considering expansion of targeted conditions. The importance of 22q11.2 is apparent given the significant clinical sequelae and prevalence, which is higher than some of the currently screened for aneuploidies. Moreover, the long-term sequalae associated with 22q11.2DS, such as autism spectrum disorder and schizophrenia, and the potential benefits of early neonatal therapy for hypocalcemia and immune deficiency, justify the consideration for prenatal screening.
In this study, authors found that modalities such as first trimester ultrasonography and traditional aneuploidy screening are not useful for the detection of 22q11.2DS. The low prevalence of individual microdeletion syndromes and the resultant low PPVs of testing have called into question the value of screening. However, the PPV of cfDNA screening for 22q11.2DS is higher and the false positive rate is lower than that associated with other accepted screening tests, such as the traditional first trimester combined screening and comparable with cfDNA screening for some of the aneuploidies.
This study identified that SNP-based cfDNA screening for 22q11.2DS can detect most affected cases, including the smaller but relatively common nested deletions, with a low false positive rate. The findings of this study provide important information when considering expansion of routine prenatal genetic screening to include screening for 22q11.2DS for all pregnant women.
Source: Dar P, Jacobsson B, Clifton R, et al. Cell-free DNA screening for prenatal detection of 22q11.2 deletion syndrome. Am J Obstet Gynecol 2022;227:79.e1-11.
