Non-Immune Hydrops Fetalis Panel

Hydrops fetalis is a condition characterized by abnormal fluid accumulation in fetal soft tissues and serous cavities. The overall incidence of hydrops fetalis is ~1/3,000 to 1/1,700 pregnancies (Norton et al. 2015. PubMed ID: 25557883; Sohan et al. 2001. PubMed ID: 11531615). Hydrops fetalis is broken into two subgroups: immune hydrops fetalis which is caused by red cell alloimmunization (RhD) and non-immune hydrops fetalis (NIHF). Immune hydrops fetalis accounts for ~10-13% of all cases of hydrops and non-immune hydrops fetalis accounts for ~87-90% of all cases of hydrops (Norton et al. 2015. PubMed ID: 25557883; Sohan et al. 2001. PubMed ID: 11531615; Bellini et al. 2009. PubMed ID: 19334091). The use of Rh(D) immune globulin has dramatically decreased the prevalence of RhD alloimmunization and subsequently associated hydrops.

The pathogenesis of NIHF is incompletely understood, however the main cause of the abnormal fluid accumulation is dysregulation of the net fluid movement between the vascular and interstitial spaces (Bellini et al. 2012. PubMed ID: 22302731). NIHF may be diagnosed anytime during pregnancy during a routine sonography or during a workup for decreased fetal movement, abnormal results on an antepartum fetal exam, or uterine size greater than expected. A clinical diagnosis of NIHF may be made when ultrasound findings indicate two or more of the following: ascites, pleural effusion, pericardial effusion, or skin edema (>5mm) (Bellini et al. 2012. PubMed ID: 22302731). Other findings consistent with NIHF include placental thickening, defined as ≥4 cm in the 2^nd trimester or >5 cm in the 3^rd trimester, and polyhydramnios (~75% of pregnancies with NIHF) (Norton et al. 2015. PubMed ID: 25557883).

The advantages of testing include identifying a disorder that may be treatable in utero, altering pregnancy or delivery management, and providing recurrence risk for future reproductive planning. The overall morbidity, mortality, and recurrence risk associated with NIHF varies widely and is determined by the underlying etiology (Crawford et al. 1988. PubMed ID: 3407692; Mardy et al. 2019. PubMed ID: 31087399; Norton et al. 2015. PubMed ID: 25557883). However, the overall perinatal mortality rate is estimated to be ~50-98% (Castillo et al. 1986. PubMed ID: 3532802; Sohan et al. 2001. PubMed ID: 11531615; Santo et al. 2011. PubMed ID: 21268039).

NIHF may be associated with chromosomal anomalies, single gene disorders, complex disorders resulting from the interaction of multiple genes, or environmental exposures (Norton et al. 2015. PubMed ID: 25557883). Mendelian forms of NIHF may be inherited in an autosomal dominant (AD), autosomal recessive (AR), and X-linked manner, or arise de novo.

The etiology of NIHF may be grouped into several large categories. Cardiovascular anomalies may account for up to 17-35% of NIHF cases and include structural anomalies, arrhythmias, and vascular abnormalities (Norton et al. 2015. PubMed ID: 25557883; Bellini et al. 2009. PubMed ID: 19334091). Thoracic and lymphatic abnormalities may account for ~10% of NIHF cases and may include congenital pulmonary airway malformations and diaphragmatic hernia (Norton et al. 2015. PubMed ID: 25557883). Severe fetal anemia accounts for ~4-12% of cases of NIHF (Mardy et al. 2019. PubMed ID: 31087399). Inborn errors of metabolism are a heterogeneous group of autosomal recessive disorders that account for ~1-2% of NIHF (Norton et al. 2015. PubMed ID: 25557883). Musculoskeletal anomalies, genitourinary and gastrointestinal malformations, placental and umbilical cord lesions, and fetal tumors account for a small proportion of NIHF (Norton et al. 2015. PubMed ID: 25557883). Several genetic syndromes have also been associated with NIHF and account for ~5-10% of all cases (Laterre et al. 2018. PubMed ID: 29500832).

Chromosomal anomalies have been reported in cases of NIHF and may account for ~7-16% of all NIHF cases (Norton et al. 2015. PubMed ID: 25557883). The most common aneuploidies seen in NIHF include Turner syndrome (~42-67%), Trisomy 21 (~23-30%), and Trisomy of chromosomes 13 or 18 (~10%) (Machin et al. 1989. PubMed ID: 2688420).

Non-genetic factors may also be causative of NIHF. The most common is parvovirus B19, responsible for 5-10% of NIHF (Norton et al. 2015. PubMed ID: 25557883). In addition, disorders unique to twin gestations, such as twin-to-twin transfusion syndrome and twin reversed arterial perfusion, may be causative of NIHF (Machin et al. 1989. PubMed ID: 2688420; Mardy et al. 2019. PubMed ID: 31087399).

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Due to the clinical and genetic heterogeneity of the disorders tested in this panel; the clinical sensitivity of this specific grouping of genes is difficult to estimate. It is estimated that 17-35% of cases are due to cardiovascular anomalies, ~10% to thoracic and lymphatic abnormalities, ~4-12% to fetal anemia, ~1-2% to inborn errors of metabolism, and a small proportion to musculoskeletal anomalies, genitourinary and gastrointestinal malformations (Bellini et al. 2009. PubMed ID: 19334091; Santo et al. 2011. PubMed ID: 21268039; Norton et al. 2015. PubMed ID: 25557883; Mardy et al. 2019. PubMed ID: 31087399). Up to 5-10% of all cases are due to genetic syndromes (Laterre et al. 2018. PubMed ID: 29500832). In addition, up to ~7-16% of NIHF cases are due to chromosomal anomalies (Machin et al. 1989. PubMed ID: 2688420; Norton et al. 2015. PubMed ID: 25557883).

Overall, the etiology of NIHF may be determined in ~60-85% of cases, while the remaining cases are considered idiopathic (Bellini et al. 2009. PubMed ID: 19334091; Bellini et al. 2009. PubMed ID: 19334092).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 97.9% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Due to the complexity of the SUZ12 gene, exons 1-9 will not be reported in this panel.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).