Expanding the fetal phenotype: Prenatal sonographic findings and perinatal outcomes in a cohort of patients with a confirmed 22q11.2 deletion syndrome

Schindewolf, Erica; Khalek, Nahla; Johnson, Mark P.; Gebb, Juliana; Coleman, Beverly G.; Crowley, T. Blaine; Zackai, Elaine H.; McDonald‐McGinn, Donna M.; Moldenhauer, Julie S.

doi:10.1002/ajmg.a.38665

Cited by 50 publications

(69 citation statements)

References 21 publications

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“…The most frequent CNV associated with cardiovascular abnormalities is deletion of chromosome 22q11.2. The most common cardiac defects of fetuses with 22q11.2 deletion syndrome are conotruncal defects, especially in interrupted aortic arch type B and in tetralogy of Fallot (Petracchi, Sisterna, Igarzabal, & Wilkins‐Haug, ; Schindewolf, Khalek, Johnson, Gebb, & Moldenhauer, ). The most common single‐gene disorder contributing to cardiac anomalies is Noonan syndrome (NS).…”

Section: Discussionmentioning

confidence: 99%

Intrauterine phenotype features of fetuses with Williams–Beuren syndrome and literature review

Yuan

Deng

Yang

et al. 2019

Annals of Human Genetics

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Williams-Beuren syndrome (WBS) is a well-defined multisystem chromosomal disorder that is caused by a chromosome 7q11.23 region heterozygous deletion. We explored prenatal diagnosis of WBS by ultrasound as well as multiple genetic methods to characterize the structural variants of WBS prenatally. Expanded noninvasive prenatal testing (NIPT-plus) was elected as a regular prenatal advanced screen for risk assessments of fetal chromosomal aneuploidy and genome-wide microdeletion/microduplication syndromes at the first trimester. At the second and three trimester, seven prenatal cases of WBS were evaluated for the indication of the invasive testing, the ultrasound features, cytogenetic, single-nucleotide polymorphism array (SNP array), and fluorescent quantitative PCR (QF-PCR) results. The NIPTplus results for seven fetuses were low risk. All cryptic aberrations were detected by the SNP array as karyotyping analyses were negative. Subsequently, QF-PCR further confirmed the seven deletions. Combining our cases with 10 prenatal cases from the literature, the most common sonographic features were intrauterine growth retardation (82.35%, 14/17) and congenital cardiovascular abnormalities (58.82%, 10/17).The manifestations of cardiovascular defects mainly involve supravalvar aortic stenosis (40%, 4/10), ventricular septal defect (30%, 3/10), aortic coarctation (20%, 2/10), and peripheral pulmonary artery stenosis (20%, 2/10). To the best of our knowledge, this is the first largest prenatal study of WBS cases with detailed molecular analysis. Aortic coarctation combined with persistent left superior vena cava and right aortic arch cardiovascular defects were first reported in prenatal WBS cases by our study.

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Section: Discussionmentioning

confidence: 99%

Intrauterine phenotype features of fetuses with Williams–Beuren syndrome and literature review

Yuan

Deng

Yang

et al. 2019

Annals of Human Genetics

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“…The prevalence of each cardiac subtype varies by study and likely reflects the diagnostic setting and age of ascertainment. In particular, fetal as compared to neonatal or older children will display a different range and severity of CHD by virtue of the age of ascertainment (Besseau‐Ayasse et al, ; Lee et al, ; Noel et al, ; Schindewolf et al, ).…”

Section: Cardiac Manifestations Of the 22q112 Deletion Syndromementioning

confidence: 99%

“…The prevalence of each cardiac subtype varies by study and likely reflects the diagnostic setting and age of ascertainment. In particular, fetal as compared to Lee et al, 2014;Noel et al, 2014;Schindewolf et al, 2018).…”

Section: Cardiac Manifestations Of the 22q11deletion Syndromementioning

confidence: 99%

22q11.2 deletion syndrome and congenital heart disease

Goldmuntz

2020

American J of Med Genetics Pt C

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The 22q11.2 deletion syndrome has an estimated prevalence of 1 in 4–6,000 livebirths. The phenotype varies widely; the most common features include: facial dysmorphia, hypocalcemia, palate and speech disorders, feeding and gastrointestinal disorders, immunodeficiency, recurrent infections, neurodevelopmental and psychiatric disorders, and congenital heart disease. Approximately 60–80% of patients have a cardiac malformation most commonly including a subset of conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B), conoventricular and/or atrial septal defects, and aortic arch anomalies. Cardiac patients with a 22q11.2 deletion do not generally experience higher mortality upon surgical intervention but suffer more peri‐operative complications than their non‐syndromic counterparts. New guidelines suggest screening for a 22q11.2 deletion in the patient with tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, conoventricular septal defects as well as those with an isolated aortic arch anomaly. Early identification of a 22q11.2 deletion in the neonate or infant when other syndromic features may not be apparent allows for timely parental screening for reproductive counseling and anticipatory evaluation of cardiac and noncardiac features. Screening the at‐risk child or adult allows for important age‐specific clinical, neurodevelopmental, psychiatric, and reproductive issues to be addressed.

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“…Nevertheless, the prevalence of fetal DGS upon prenatally occurrence of urogenital malformations may even be higher, but, as being the reason for possibly missed cases likewise in our study, isolated second‐trimester markers have only small effects on modifying the pretest odds for aneuploidy . This, together with hereof subsequent prenatal counseling, is most probably accountable for the relative high rate of parent's refusal of invasive genetic testing, hence, highlighting the recent suggestion of diagnostic testing for all fetuses with any structural malformation particularly when fetal heart defects are not isolated by Schindewolf et al They reported a prenatal series of 22q11.2DS cases presenting with CHD associated with extracardiac findings in 90% including central nervous system (CNS), gastrointestinal, genitourinary, pulmonary, facial, skeletal, thymus abnormalities, and polyhydramnios, as well as a case of SUA but none with IUGR . Since we found similar extracardiac associations, this compelled us to reevaluate our management with the consideration of widened fetal genotype analysis and intercessional counseling.…”

Section: Discussionmentioning

confidence: 85%

DiGeorge syndrome chromosome region deletion and duplication: Prenatal genotype‐phenotype variability in fetal ultrasound and MRI

2019

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Objective The aim of the study was to assess genotype‐phenotype correlation of prenatally diagnosed fetal DGS and dup22q11 syndrome by fetal molecular genetic analysis, fetal ultrasound, and/or MRI. Methods In this retrospective consecutive case series, pregnant women were screened for fetal anomalies during a period of 10 years. Fetal genotype was assessed in 72 cases upon the occurrence of five prenatal fetal phenotypic features: cardiac anomalies, hypo/aplastic thymus, craniofacial malformations, urinary abnormalities, or IUGR; genotype‐phenotype correlation was tested to potentially improve prenatal diagnosis of fetal DGS and dup22q11 syndrome. Results Fetal genotypes of deletions or duplications in proximal clusters of LCR22s (A‐B) were associated with fetal cardiac anomalies in combination with hypo/aplastic thymus and craniofacial malformations, suggesting a correlation with deleted HIRA. TOF associated with aplastic thymus in combination with renal defects indicated a relevant correlation with TBX1 deletion. Deletions in central LCR22s (B‐D) with the loss of CRKL supposed a trend of genotype‐phenotype correlation with fetal urinary abnormalities. Conclusion Genotype‐phenotype correlation might improve prenatal diagnosis of fetal DGS and dup22q11 syndrome. Hence, prenatal screening and counseling is highly enhanced by a combination of fetal molecular genetic analysis, fetal ultrasound, and/or MRI. The implications of these findings remain to be explored.

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Expanding the fetal phenotype: Prenatal sonographic findings and perinatal outcomes in a cohort of patients with a confirmed 22q11.2 deletion syndrome

Cited by 50 publications

References 21 publications

Intrauterine phenotype features of fetuses with Williams–Beuren syndrome and literature review

Intrauterine phenotype features of fetuses with Williams–Beuren syndrome and literature review

22q11.2 deletion syndrome and congenital heart disease

DiGeorge syndrome chromosome region deletion and duplication: Prenatal genotype‐phenotype variability in fetal ultrasound and MRI

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