Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder

Hakami, Fahad; Dillon, Mitchell W.; Lebo, Matthew S.; Mason‐Suares, Heather

doi:10.1002/pd.4797

Cited by 28 publications

(41 citation statements)

References 34 publications

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“…Therefore, they are easily overlooked in pregnancy and might not be confined to only fetuses with a RIT1 mutation. SOS1 has to our knowledge only been described a handful of times before in the prenatal setting, 15 and in our study only one fetus showed a pathogenic variant. This…”

Section: Genesmentioning

confidence: 37%

Prenatal ultrasound findings of rasopathies in a cohort of 424 fetuses: update on genetic testing in the NGS era

et al. 2019

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BackgroundThis study evaluates 6 years of prenatal rasopathy testing in the Netherlands, updates on previous data and gives recommendations for prenatal rasopathy testing.Methods424 fetal samples, sent in for prenatal rasopathy testing in 2011–2016, were collected. Cohort 1 included 231 samples that were sequenced for 1–5 rasopathy genes. Cohort 2 included 193 samples that were analysed with a 14-gene next generation sequencing (NGS) panel. For all mutation-positive samples in both cohorts, the referring physician provided detailed ultrasound findings and postnatal follow-up. For 168 mutation-negative samples in cohort 2, solely clinical information on the requisition form was collected.ResultsIn total, 40 (likely) pathogenic variants were detected (9.4%). All fetuses showed a variable degree of involvement of prenatal findings: increased nuchal translucency (NT)/cystic hygroma, distended jugular lymph sacs (JLS), hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies. An increased NT was the most common finding. Eight fetuses showed solely an increased NT/cystic hygroma, which were all larger than 5.5 mm. Ascites and renal anomalies appeared to be poor predictors of pathogenic outcome.ConclusionFetuses with a rasopathy show in general multiple ultrasound findings. The larger the NT and the longer it persists, the more likely it is to find a pathogenic variant. Rasopathy testing is recommended when the fetus shows an isolated increased NT ≥5.0 mm or when NT of ≥3.5 mm and at least one of the following ultrasound anomalies is present: distended JLS, hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies.

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Section: Genesmentioning

confidence: 37%

Prenatal ultrasound findings of rasopathies in a cohort of 424 fetuses: update on genetic testing in the NGS era

et al. 2019

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“…This highlights the importance of RD testing when NT is clearly abnormal, as clinicians can provide a definitive diagnosis and inform parents regarding recurrence risk, especially when there are additional ultrasound findings. The inclusion in previous studies of pregnancies already suspected to have RD may be a reason for the lower detection rate in our study. A recent study with a clinical algorithm similar to ours showed a 10.3% (4/39) detection rate.…”

Section: Discussionmentioning

confidence: 84%

“…Previous studies testing for RD in cases with increased NT showed an incidence of 10%-26% 14,15,29 . In this study cohort, there was a 2.9% detection rate of pathogenic variants on RD testing, all of which were de novo and were detected in cases with NT > 6.0 mm.…”

Section: Discussionmentioning

confidence: 94%

Microarray and RASopathy‐disorder testing in fetuses with increased nuchal translucency

Sinajon

Chitayat

Roifman

et al. 2020

Ultrasound in Obstet & Gyne

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Objectives To determine the incidence of chromosomal abnormalities, submicroscopic chromosomal abnormalities and RASopathy‐disorder (RD) pathogenic variants in a cohort of pregnancies with nuchal translucency thickness (NT) ≥ 3.5 mm, and to propose a clinical protocol for surveillance of this group of patients. Methods This was a retrospective chart review of patients referred to The Prenatal Diagnosis and Medical Genetics Program at Mount Sinai Hospital between January 2013 and December 2015, due to NT ≥ 3.5 mm, who underwent chorionic villus sampling or amniocentesis. Patients underwent extensive genetic counseling prior to invasive procedures and testing. Quantitative fluorescence polymerase chain reaction (QF‐PCR) was performed as the first‐line test for aneuploidy. If the result was negative, patients underwent karyotyping and/or chromosomal microarray analysis (CMA), and if the findings were normal, they had testing for RD pathogenic variants, which included nine known genes. Patients also underwent detailed fetal ultrasound examinations and echocardiography, performed by expert operators. Results A total of 226 eligible patients were identified. In 116/226 (51.3%) patients, QF‐PCR identified a chromosomal aneuploidy. The remaining 110/226 (48.7%) patients had further genetic testing. Karyotyping/CMA detected an abnormal/pathogenic cytogenetic result in 9/110 (8.2%) patients, as well as five variants of unknown significance (VOUS). RD testing yielded three pathogenic variants (3/103), giving a detection rate of 2.9%, and one VOUS. The optimal NT cut‐off for RD screening was 7.9 mm in this population. In 92/110 (83.6%) patients, the genetic investigations were normal. Of these pregnancies, an early (14–16 weeks' gestation) detailed fetal ultrasound examination identified a structural abnormality in 24 (26.1%), 15 (16.3%) had an abnormal detailed ultrasound examination at 18–22 weeks' gestation and fetal echocardiography showed a cardiac abnormality in nine (9.8%). The birth outcome in the 83 pregnancies that had normal genetic investigations and known outcome included seven (8.4%) cases of termination of pregnancy, seven (8.4%) cases of intrauterine fetal death and 69 (83.1%) cases of live birth. Nine (9.8%) patients were lost to follow‐up. Conclusions Both CMA and molecular testing for RD are important investigations in pregnancies with NT ≥ 3.5 mm. The use of genetic testing combined with fetal ultrasound examination provides valuable information that can influence pregnancy outcome, and provide recurrence risks, in this patient population. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

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“…The most common single‐gene disorder contributing to cardiac anomalies is Noonan syndrome (NS). Prenatally, a congenital heart defect like pulmonary valve stenosis was the most common fetal finding detected in molecularly confirmed NS newborns, followed by cystic hygroma and then increased nuchal translucency (Croonen, Nillesen, Stuurman, & Yntema, ; Hakami, Dillon, Lebo, & Mason‐Suares, ). From the findings of our study and literature review, the most familiar and representative intrauterine phenotypes of WBS were IUGR combined with cardiovascular abnormalities (particularly with SVAS).…”

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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Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder

Cited by 28 publications

References 34 publications

Prenatal ultrasound findings of rasopathies in a cohort of 424 fetuses: update on genetic testing in the NGS era

Prenatal ultrasound findings of rasopathies in a cohort of 424 fetuses: update on genetic testing in the NGS era

Microarray and RASopathy‐disorder testing in fetuses with increased nuchal translucency

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

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