Utility of chromosomal microarray for diagnosis in cases of nonimmune hydrops fetalis

Mardy, Anne H.; Rangwala, Naseem; Hernandez-Cruz, Yessenia; Gosnell, Kristen; González, Juan M.; Norton, Mary E.; Sparks, Teresa N.

doi:10.1002/pd.5617

Cited by 14 publications

(18 citation statements)

References 21 publications

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“…Thus, chromosomal abnormalities, if not the foremost cause, are an important cause accounting for a significant proportion of the diagnoses in most studies. CMA did not offer any benefit in identifying additional chromosomal abnormalities in our cohort, consistent with observations by Sparks et al 44 . However, Deng et al.…”

Section: Discussionsupporting

confidence: 92%

Utility of fetal whole exome sequencing in the etiological evaluation and outcome of nonimmune hydrops fetalis

et al. 2021

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Introduction Nonimmune hydrops fetalis (NIHF) has varied etiology. We assessed the etiological spectrum and evaluated the utility of fetal whole exome sequencing (fWES) for the diagnosis of NIHF. Methods In this prospective cohort study, we evaluated antenatally diagnosed fetuses with NIHF between July 2018 and December 2019 according to the routine diagnostic algorithm. Fetuses that remained undiagnosed after routine NIHF workup were subjected to fetal chromosomal microarray and/or WES. Pregnancies were followed up for clinical outcomes. Results Of the 45 fetuses, consanguinity and recurrent hydrops fetalis were observed in 13.3% (6/45) and 28.8% (13/45), respectively. Overall, an etiological diagnosis was possible in 75.5% (34/45) of fetuses, while the cause remained unknown in 24.4% (11/45). A genetic etiology was identified in 46.6% (21/45): aneuploidy and monogenic disorders in 28.8% (13/45) and 17.8% (8/45), respectively. fWES on 19 fetuses detected disease‐causing variants in 42.1% (8/19). Nine novel variants were detected in RAPSN, ASCC1, NEB, PKD1L1, GUSB, and PIEZO1. Only 8.8% (4/45) of the cohort survived without morbidity. Conclusions This study describes the etiological spectrum and the disease‐causing variants in an Indian cohort of hydropic fetuses.

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Section: Discussionsupporting

confidence: 92%

Utility of fetal whole exome sequencing in the etiological evaluation and outcome of nonimmune hydrops fetalis

et al. 2021

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“…The role of QF-PCR or conventional karyotyping in NIHF should always be respected, given the high incidence of aneuploidy 38 . However, given the limited additional yield of CMA over karyotyping, and considering the ability of WGS to detect both structural variants and aneuploidy, it may be reasonable in the future to consider WGS as the second-line test after QF-PCR 5 . The list of novel causative genes in NIHF is constantly expanding and, over time, the yield of prenatal NGS will likely improve as more genes are discovered and our understanding of the prenatal phenotype develops 2,37 .…”

Section: Mone Et Almentioning

confidence: 99%

“…Excluding cases due to infection, fetal structural anomaly (FSA) or complications of twin pregnancy, aneuploidy may explain one-quarter of cases, with chromosomal microarray analysis (CMA) demonstrating copy-number variants (CNVs) in a further 6-14% of cases 3,4 . Despite this, the definitive diagnostic yield of CMA over standard G-banding karyotyping is moderate and, following exclusion of the aforementioned causes, up to 50% of cases of NIHF remain unexplained, with a significant proportion thought to be secondary to single-gene variants 5 . Over 170 genes have been identified as being associated with NIHF and, until the recent emergence of next-generation sequencing (NGS), testing for such conditions has relied on targeted gene testing and enzyme assays 3,6 .…”

Section: Introductionmentioning

confidence: 99%

Fetal hydrops and the Incremental yield of Next‐generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta‐analysis

Mone

Eberhardt

Hurles

et al. 2021

Ultrasound in Obstet & Gyne

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Objective To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non‐immune hydrops fetalis (NIHF). Methods A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and http://ClinicalTrials.gov databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound‐based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two vs three or more cavities affected). Results In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7/28) in all NIHF cases, 21.4% (3/14) in those with isolated NIHF and 28.6% (4/14) in those with non‐isolated NIHF. In the meta‐analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95% CI, 24–34%; P < 0.00001; I2 = 0%) in all NIHF, 21% (95% CI, 13–30%; P < 0.00001; I2 = 0%) in isolated NIHF and 39% (95% CI, 30–49%; P < 0.00001; I2 = 1%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27/89) of cases with a causative pathogenic variant, most frequently due to a PTPN11 variant (44.4%; 12/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51/89), with most being de novo (86.3%; 44/51). Conclusions Use of prenatal next‐generation sequencing in both isolated and non‐isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole‐genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

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“…Standard genetic testing with karyotyping or chromosomal microarray analysis identifies the cause of only 25% of NIHF cases and does not detect single-gene disorders. [12][13][14][15][16][17][18][19][20][21][22][23][24][25] The contribution of single-gene disorders to NIHF is unknown but is potentially substantial. Some genetic disorders underlying NIHF portend mild long-term outcomes, whereas others are lethal despite treatment.…”

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confidence: 99%

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

et al. 2020

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BACKGROUNDThe cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear. METHODSWe evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited. RESULTSIn 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases. CONCLUSIONSIn this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases.

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Utility of chromosomal microarray for diagnosis in cases of nonimmune hydrops fetalis

Cited by 14 publications

References 21 publications

Utility of fetal whole exome sequencing in the etiological evaluation and outcome of nonimmune hydrops fetalis

Utility of fetal whole exome sequencing in the etiological evaluation and outcome of nonimmune hydrops fetalis

Fetal hydrops and the Incremental yield of Next‐generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta‐analysis

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

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