The utility of exome sequencing for fetal pleural effusions

Jelin, Angie C.; Sobreira, Nara; Wohler, Elizabeth; Solomon, Benjamin; Sparks, Teresa N.; Sagaser, Katelynn G.; Forster, Katherine R; Miller, Jena L.; Witmer, P. Dane; Hamosh, Ada; Valle, David

doi:10.1002/pd.5650

Cited by 11 publications

(10 citation statements)

References 26 publications

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“…In our study, the lower detection rate of ES (16.7%) might be due to the fact that most of the cases were primary hydrothorax, which was caused by erroneous lymphatic formation and reabsorption and was rarely associated with genetic diseases. In a recent study, Jelin et al [23] performed ES in 6 cases with unexplained pleural effusions, and a pathogenic variant was identified in 1 case (16.7%), which was consistent with our study. Furthermore, in the present study, ES results were all negative in neonatal survivors, while the proportion of abnormal ES in neonatal death was as high as 60%.…”

Section: Discussionsupporting

confidence: 92%

The Value of Exome Sequencing in Thoracoamniotic Shunt for Severe Pleural Effusion with Fetal Hydrops: A Retrospective Clinical Study

Wei¹,

Zhou²,

Zhou³

et al. 2022

Fetal Diagn Ther

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Objective To study the value of exome sequencing (ES) in severe pleural effusion with non-immune hydrops fetalis (NIHF) that underwent thoracoamniotic shunt (TAS). Methods It was a retrospective study of NIHF that underwent TAS between 2012 and 2020 at Shanghai First Maternity and Infant Hospital. After a detailed assessment, NIHF cases with aneuploidies, infections, and structural anomalies were excluded, and TAS was offered to cases with severe pleural effusion. Quantitative fluorescence polymerase chain reaction (QF-PCR) was conducted to exclude Trisomy 21, 18 and 13 before fetal therapy, and chromosomal microarray analysis (CMA) was offered to all the cases. Before 2019, ES was retrospectively performed using stored fetal DNA extracted from prenatal samples; from 2019 onwards, ES was discussed and offered before intrauterine therapies. Results A total of 18 NIHF cases underwent TAS with negative CMA and continuing pregnancy were included. Fetal hydrops was relieved in 16 cases (88.9%). The median gestational ages at intervention and at delivery were 31.2 (22.0~33.1) weeks and 34.3 (29.7~38.6) weeks, respectively. The neonatal survival rate was 72.2% (13/18) and no causative gene variants were identified from ES in any survivors. Pathogenic or likely pathogenic variants were detected in 3 out of 5 neonatal deaths. If rapid ES could have been available to guide fetal therapy, the neonatal survival rate after TAS would have increased from 72.2% to 86.7%. Conclusions Single gene disorders was one of the major causes of perinatal death in NIHF cases that underwent fetal therapy. Prenatal rapid exome sequencing may be of good promise in NIHF to exploring precise etiology and guide fetal therapy.

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Section: Discussionsupporting

confidence: 92%

The Value of Exome Sequencing in Thoracoamniotic Shunt for Severe Pleural Effusion with Fetal Hydrops: A Retrospective Clinical Study

Wei¹,

Zhou²,

Zhou³

et al. 2022

Fetal Diagn Ther

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Section: Study or Subgroupmentioning

confidence: 99%

“…Test for overall effect: Z = 5.15 (P < 0.00001) Heterogeneity: tau 2 = 0.00; chi 2 = 4.75, df = 11 (P = 0.94); I 2 = 0% -0.5 1.8% 6.3% Stals (2018) 23 Westerfield (2015) 30 Westphal (2019) 24 Zhou (2020) 17 Corsten-Janssen (2020) 32 Study or subgroup Boissel (2018) 18 Deden (2020) 27 Deng (2020) 19 Greenbaum (2019) 28 Jelin (2020) 20 Lord (2019) 8 Mone (2020) 34 Petrovski (2019) 16 Sparks (2020) 2 0 45 109 109 100.0% 0.39 (0.30, 0.49) Total (95% CI)…”

Section: Total Eventsmentioning

confidence: 99%

“…For the study of Petrovski et al 16 , based in Columbia University Medical Centre, New York, USA, the authors provided an extended dataset. In total, in addition to the extended PAGE study cohort, a further 20 studies met the inclusion criteria (Figure 1) 2,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] . Table 1 shows the characteristics of the included studies and Figure 2 shows the overall quality assessment.…”

Section: Systematic Review and Meta-analysismentioning

confidence: 99%

“…Becher (2020) 26 Boissel (2018) 18 Corsten-Janssen (2020) 32 Croonen (2013) 33 Deden (2020) 27 Deng (2020) 19 Greenbaum (2019) 28 Jelin (2020) 20 Lord (2019) 8 Mone (2020) 34 Normand (2018) 21 Petrovski (2019) 16 Sparks (2019) 29 Sparks (2020) 2 Stals (2018) 23 Vora (2017) 22 Westerfield (2015) 30 Westphal (2019) 24 Yang (2012) 31 Yates (2017) 25 Zhou (2020) 17 17 Study or subgroup Becher (2020) 26 Corsten-Janssen (2020) 32 Deden (2020) 27 Deng (2020) 19 Greenbaum (2019) 28 Jelin (2020) 20 Lord (2019) 8 Mone (2020) 34 1.8% 6.3% 23 Westerfield (2015) 30 Westphal (2019) 24 Zhou (2020) 17 Corsten-Janssen (2020) 32 Study or subgroup Boissel (2018) 18 Deden (2020) 27 Deng (2020) 19 Greenbaum (2019) 28 Jelin (2020) 20 Lord (2019) 8 Mone (2020) 34 Petrovski (2019) 16 Sparks (2020) The findings of the extended PAGE cohort and the systematic review were broadly concordant, but with a lower incremental yield of ES in the cohort study, which may be explained by the smaller number of cases as well as the unselected approach to case selection. The high incidence of RASopathies and of de-novo varian...…”

Section: Study or Subgroupmentioning

confidence: 99%

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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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A novel RYR1 variant in an infant with a unique fetal presentation of central core disease

Baker

Gharaibeh

Bove

et al. 2023

American J of Med Genetics Pt A

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Ryanodine receptor type 1‐related disorder (RYR1‐RD) is the most common subgroup of congenital myopathies with a wide phenotypic spectrum ranging from mild hypotonia to lethal fetal akinesia. Genetic testing for myopathies is imperative as the diagnosis informs counseling regarding prognosis and recurrence risk, treatment options, monitoring, and clinical management. However, diagnostic challenges exist as current options are limited to clinical suspicion prompting testing including: single gene sequencing or familial variant testing, multi‐gene panels, exome, genome sequencing, and invasive testing including muscle biopsy. The timing of diagnosis is of great importance due to the association of RYR1‐RD with malignant hyperthermia (MH). MH is a hypermetabolic crisis that occurs secondary to excessive calcium release in muscles, leading to systemic effects that can progress to shock and death if unrecognized. Given the association of MH with pathogenic variants in RYR1, a diagnosis of RYR1‐RD necessitates an awareness of medical team to avoid potentially triggering agents. We describe a case of a unique fetal presentation with bilateral diaphragmatic eventrations who had respiratory failure, dysmorphic facial features, and profound global hypotonia in the neonatal period. The diagnosis was made at several months of age, had direct implications on her clinical care related to anticipated need to long‐term ventilator support, and ultimately death secondary an arrhythmia as a result of suspected MH. Our report reinforces the importance of having high suspicion for a genetic syndrome and pursuing early, rapid exome or genome sequencing as first line testing in critically ill neonatal intensive care unit patients and further evaluating the pathogenicity of a variant of uncertain significance in the setting of a myopathic phenotype.

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The utility of exome sequencing for fetal pleural effusions

Cited by 11 publications

References 26 publications

The Value of Exome Sequencing in Thoracoamniotic Shunt for Severe Pleural Effusion with Fetal Hydrops: A Retrospective Clinical Study

The Value of Exome Sequencing in Thoracoamniotic Shunt for Severe Pleural Effusion with Fetal Hydrops: A Retrospective Clinical Study

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

A novel RYR1 variant in an infant with a unique fetal presentation of central core disease

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