Fetal pleural effusion: Contemporary methods of genetic evaluation

Abstract

Objective To determine the contribution of chromosomal microarray (CMA) and other advanced genetic tests to the genetic evaluation of fetal pleural effusion (FPE) and to identify parameters that might assist in predicting genetic abnormality. Methods A retrospective study of FPE cases referred between 2013 and 2018 was conducted. Cases that underwent genetic evaluation were divided into two groups, chromosomally normal and genetically abnormal. The types and prevalence of genetic abnormalities were reported. Clinical and sonographic parameters were compared. Univariate and multivariate analyses were performed to determine an association between different parameters and genetic abnormality. Results Sixty‐two cases were included in the study. Forty‐eight cases were genetically assessed (karyotype, CMA, whole exome sequencing, Noonan panel, or a combination). A clinically significant genetic abnormality was detected in 29.17% (14/48) of cases. Aneuploidy and single gene disorders were found in 78.6% (11/14) and 21.4% (3/14) of abnormal cases. Four additional cases had microdeletion/duplications detected, yet none were of clinical significance. Multivariate analysis indicated that the presence of anomalies was statistically associated with genetic abnormality (95% CI, 1.144‐168.2; 0.039). Conclusion In our cohort, CMA did not demonstrate an additional clinical yield over karyotyping. The presence of anomalies was independently associated with underlying genetic abnormality.

Prenatal phenotype of Kabuki syndrome: A case series and literature review

“…Ultrasound scans showed a range of abnormalities including increased nuchal translucency, pleural effusion, cardiac anomaly, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. Similar antenatal presentations were also noted in the recent large case series and published case reports 8–40 . More than half of the cases were diagnosed after birth by clinical assessment and molecular testing.…”

A homozygous variant in growth and differentiation factor 2 (GDF2) may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis

“…Fourth, with SNP-array analysis and massive parallel sequencing other major genetic causes of NIHF were excluded. This included hematological disease, chromosomal aneuploidies, and variants in genes known to cause lymphatic dysplasia including RASopathies, (generalized) lymphedema, or inborn errors of metabolism (Bellini et al, 2015;Hakami, Dillon, Lebo, & Mason-Suares, 2016;Houweling et al, 2010;Johnston et al, 2018;Joyce et al, 2016;Mardy et al, 2019;Martin-Almedina et al, 2016;Mason-Suares et al, 2017;Meng et al, 2019;Moreno et al, 2013;Pagnamenta et al, 2019;Quinlan-Jones et al, 2019;Stuurman et al, 2019;Sudrie-Arnaud et al, 2018;Weissbach et al, 2019;Yates et al, 2017). Finally, no other causes for the NIHF, such as intra-uterine infections and cardiac abnormalities, were present.…”

“…Cardiovascular anomalies are the most frequent cause of NIHF (≈20%). Genetic disorders may also lead to NIHF and include a wide spectrum of diseases, including chromosomal aneuplodies (trisomies, monosomy X, triploidy), hematological diseases (α-thalassemia), monogenic syndromes (RASopathies, Kabuki syndrome), inborn errors of metabolism (lysosomal storage disease) and lymphatic dysplasia (Bellini et al, 2015;Mardy et al, 2019;McPherson, 2019;Moreno et al, 2013;Quinlan-Jones et al, 2019;Weissbach et al, 2019). Few familial cases of nonimmune hydrops fetalis have been described and in some of the cases with lymphatic dysplasia and/or lymphangiectasia bi-allelic variants in CCBE1, ADAMTS3, FAT4, CAL-CRL, and PIEZO1 have been reported (Alders et al, 2009;Alders et al, 2014;Brouillard et al, 2017;Datkhaeva et al, 2018;Delabaere et al, 2008;Fotiou et al, 2015;Jacquemont, Barbarot, Boceno, Stalder, & David, 2000;Mackie et al, 2018;Njolstad, Reigstad, Westby, & Espeland, 1998;Stevenson, Pysher, Ward, & Carey, 2006;Wieacker, Muschke, Pollak, & Muller, 2005).…”

The utility of exome sequencing for fetal pleural effusions

“…Amniocentesis or chorionic villus sampling is offered for chromosomal microarray, infectious evaluation, and potentially molecular gene panel testing, which includes RASopathies and metabolic conditions. Noonan syndrome is a known cause of fetal pleural effusions and has been diagnosed in similar cohorts by panel testing and whole exome sequencing . A diagnosis is unattainable in many cases, however, despite these laboratory evaluations.…”

“…Recently, ES has identified additional candidate genes in cases with fetal pleural effusions. Reported cases involve rare single nucleotide variant changes in genes involved in biological pathways suggestive of causation, including LZTR1 , RIT1 , KMT2D , and EPHB4 . In the current study, our primary goal was to identify the clinical yield of ES in fetuses with fetal pleural effusions of unclear etiology.…”