Positive cfDNA screening results for 22q11.2 deletion syndrome—Clinical and laboratory considerations

Soster, Erica; Dyr, Brittany; Rafalko, Jill; Almasri, Eyad; Cacheris, Phillip

doi:10.3389/fgene.2023.1146669

Cited by 5 publications

(17 citation statements)

References 36 publications

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“…Non-invasive prenatal testing (NIPT) as a screening for microdeletion syndromes has gained importance in recent years, although it is not yet offered as a routine test due to having a low sensitivity of 75% and low positive predictive value (PPV) of 23.7% for 22q11.2 in particular [ 1 ]. Nevertheless, the rate of prenatally detected 22q11.2 DS without abnormal US findings is likely to increase substantially during the coming years, as the use of NIPT as well as its diagnostic accuracy for microdeletion syndromes are expected to change [ 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical Course and Outcome of Prenatally Detected 22q11.2 Deletion Syndrome—A Retrospective Analysis

et al. 2023

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The 22q11.2 deletion syndrome (22q11.2 DS) is known as the most common microdeletion syndrome. Due to its variable clinical phenotype, prenatal diagnosis can be challenging. The aim of this retrospective study was to evaluate the clinical course and pregnancy outcome of cases with prenatally diagnosed 22q11.2 deletion syndrome (DS) as well as to evaluate the role of prenatal magnetic resonance imaging (MRI) and postmortem examination. In total, 21 cases who underwent prenatal ultrasound examination and pregnancy care at the Department of Obstetrics and Gynecology at the Medical University of Vienna between 2012 and 2022 were included. The majority of the cases were genetically diagnosed using fluorescent in situ hybridization (FISH). The median gestational age (GA) at genetic diagnosis was 23.0 weeks (IQR 21.4–24.8 weeks). CHDs were detected in all fetuses and the most common extracardiac manifestation was thymus hypo/aplasia followed by genitourinary anomalies. Prenatal magnetic resonance imaging (MRI) revealed additional diagnostic information in three of ten cases. Overall, 14 patients opted for drug-induced TOP, of which 9 cases had a feticide prior to the induction of labor. The majority of craniofacial malformations were only detected by autopsy. In conclusion, the majority of cases prenatally diagnosed with 22q11.2 DS had an absent or hypoplastic thymus noted antenatally in addition to the detected CHD, and almost half of the cases had another extracardiac malformation of predominantly genitourinary origin. Furthermore, prenatal MRIs confirmed previously detected malformations, but only provided additional diagnostic information in three out of ten cases, whereas postmortem examination diagnosed most of the craniofacial anomalies and should always be conducted, serving as an important quality indicator for prenatal imaging.

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Section: Discussionmentioning

confidence: 99%

Clinical Course and Outcome of Prenatally Detected 22q11.2 Deletion Syndrome—A Retrospective Analysis

et al. 2023

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“…Sensitivity to detect the 22q11.2 microdeletion was reported as 83%, specificity 99%, and PPV 52.6% 72 . Although this PPV exceeded that reported for trisomy 13 (37.2%) in an evidence based review, 73 disproportionate uptake of screening in situations where suggestive anatomic features are already identified will affect the PPV 10,74 …”

Section: Introductionmentioning

confidence: 87%

“…72 Although this PPV exceeded that reported for trisomy 13 (37.2%) in an evidence based review, 73 disproportionate uptake of screening in situations where suggestive anatomic features are already identified will affect the PPV. 10,74 Imperfect sensitivity means that a negative cfDNA screening result does not eliminate the possibility of a 22q11.2 microdeletion in the fetus, especially in the case of smaller, for example, nested deletions (Figure 1). Particularly in the context of one or more features of 22q11.2DS with a negative cfDNA screening result, definitive prenatal diagnostic testing should be considered.…”

Section: Prenatal Genetic Screening For 22q112dsmentioning

confidence: 99%

“…A positive cfDNA result cannot distinguish between a 22q11.2 microdeletion that is maternally or fetally derived, or both. A recent study reported that in many instances the maternal 22q11.2 microdeletion was apparently unknown (or the diagnosis not recorded) prior to prenatal cfDNA genetic screening 74 . Similarly, if the mother is not known to carry a 22q11.2 microdeletion but a negative prenatal definitive diagnostic test (i.e.…”

Section: Introductionmentioning

confidence: 99%

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Prenatal cardiac findings and 22q11.2 deletion syndrome: Fetal detection and evaluation

Goldmuntz,

Bassett,

Boot

et al. 2024

Prenatal Diagnosis

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Clinical features of 22q11.2 microdeletion syndrome (22q11.2DS) are highly variable between affected individuals and frequently include a subset of conotruncal and aortic arch anomalies. Many are diagnosed with 22q11.2DS when they present as a fetus, newborn or infant with characteristic cardiac findings and subsequently undergo genetic testing. The presence of an aortic arch anomaly with characteristic intracardiac anomalies increases the likelihood that the patient has 22q11.2 DS, but those with an aortic arch anomaly and normal intracardiac anatomy are also at risk. It is particularly important to identify the fetus at risk for 22q11.2DS in order to prepare the expectant parents and plan postnatal care for optimal outcomes. Fetal anatomy scans now readily identify aortic arch anomalies (aberrant right subclavian artery, right sided aortic arch or double aortic arch) in the three‐vessel tracheal view. Given the association of 22q11.2DS with aortic arch anomalies with and without intracardiac defects, this review highlights the importance of recognizing the fetus at risk for 22q11.2 deletion syndrome with an aortic arch anomaly and details current methods for genetic testing. To assist in the prenatal diagnosis of 22q11.2DS, this review summarizes the seminal features of 22q11.2DS, its prenatal presentation and current methods for genetic testing.

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“…5,6 Assessment for microdeletion syndromes, including 22q11.2DS, is available on some non-invasive prenatal screening panels with a positive predictive value for 22q between 23.7% and 52.6%. [9][10][11] Given the broad phenotypic presentation and the long-term clinical implications of the diagnosis, identification of fetal sonographic markers that may be associated with 22q11.2DS may enhance ascertainment. Extra-cardiac sonographic markers such as dilated CSP and small thymus have been proposed in small case series as components of the fetal phenotype of 22q11.2DS.…”

Section: Introductionmentioning

confidence: 99%

Enlarged cavum septum pellucidum and small thymus as markers for 22q11.2 deletion syndrome

Gaiser,

Schindewolf,

Conway

et al. 2024

Prenatal Diagnosis

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BackgroundEnlarged cavum septum pellucidum (CSP) and hypoplastic thymus are proposed extra‐cardiac fetal markers for 22q11.2 deletion syndrome. We sought to determine if they were part of the fetal phenotype of our cohort of fetuses with 22q11.2 deletion syndrome.MethodsCase‐control study of fetuses evaluated from 2016 to 2022. The study group included fetuses with laboratory confirmation of 22q11.2 deletion syndrome. The control group included pregnancies with conotruncal cardiac anomalies with normal microarray as well as structurally normal fetuses with normal microarray. The CSP and thymus were routinely measured during anatomical ultrasound in all patients at their initial visit at 27.1 ± 4.7 weeks. The CSP and thymus measurements were classified as abnormal if they were >95% or <5% for gestational age, respectively. The groups were compared using analysis of variance or Kruskal‐Wallis for continuous variables and Fisher's exact test for categorical variables. Logistic regression was performed, and a Receiver Operating Characteristic (ROC) curve was constructed.ResultsWe identified 47 fetuses with 22q11.2 deletion syndrome and compared them to 47 fetuses with conotruncal anomalies and normal microarray and 47 structurally normal fetuses with normal microarray. 51% (24/47) of fetuses with 22q11.2 deletion syndrome had an enlarged CSP compared to 6% (3/47) of fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p < 0.001). Of the fetuses with 22q11.2 deletion syndrome, 83% (39/47) had a hypoplastic or absent thymus compared to 9% (4/47) of the fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p < 0.001). 87% (41/47) of the fetuses with 22q11.2 deletion syndrome had conotruncal cardiac anomalies. Logistic regression revealed that both enlarged CSP and hypoplastic/absent thymus were associated with 22q11.2 deletion syndrome. The area under the ROC curve for the two markers was 0.94.ConclusionAn enlarged CSP and hypoplastic/absent thymus appear to be part of the fetal phenotype of 22q11.2 deletion syndrome. These markers are associated with conotruncal anomalies in the setting of 22q11.2 deletion syndrome but not in normal controls or fetuses with conotruncal defects and normal microarrays.

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Positive cfDNA screening results for 22q11.2 deletion syndrome—Clinical and laboratory considerations

Cited by 5 publications

References 36 publications

Clinical Course and Outcome of Prenatally Detected 22q11.2 Deletion Syndrome—A Retrospective Analysis

Clinical Course and Outcome of Prenatally Detected 22q11.2 Deletion Syndrome—A Retrospective Analysis

Prenatal cardiac findings and 22q11.2 deletion syndrome: Fetal detection and evaluation

Enlarged cavum septum pellucidum and small thymus as markers for 22q11.2 deletion syndrome

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