A systematic review of monogenic etiologies of nonimmune hydrops fetalis

Abstract

Hydrops Fetalis (HF), accumulation of fluid in two or more fetal compartments, is life-threatening to the fetus. Genetic etiologies include many chromosomal and monogenic disorders. Despite this, the clinical workup typically evaluates limited genetic targets. To support broader molecular testing of pregnancies with HF, we cataloged the spectrum of monogenic disorders associated with nonimmune hydrops fetalis (NIHF). We performed a systematic literature review under PROSPERO tag CRD42018099495 of cases reporting NIHF meeting strict phenotypic criteria and well-defined genetic diagnosis. We ranked the evidence per gene based on number of reported cases, phenotype and molecular/biochemical diagnosis. We identified 131 genes with strong evidence for an association with NIHF and 46 genes with emerging evidence spanning the spectrum of multisystem syndromes, cardiac disorders, hematologic disorders, and metabolic disorders. Several genes previously implicated with NIHF did not have any reported cases in the literature with both fetal hydrops and molecular diagnosis. Many genes with strong evidence for association with NIHF would not be detected using current sequencing panels. Nonimmune HF has many possible monogenic etiologies, several with treatment implications, but current diagnostic approaches are not exhaustive. Studies are needed to assess if broad sequencing approaches like whole exome sequencing are useful in clinical management of HF.

Case Report: Whole Exome Sequencing Revealed Two Novel Mutations of PIEZO1 Implicated in Nonimmune Hydrops Fetalis

“…Even though, it is still a challenging task to elucidate the exact etiology of NIHF, which is essential for prenatal counseling and determination of the appropriate therapy if available (Norton et al, 2015). In recent years, whole exome sequencing (WES) has been gradually applied to identify de-novo mutations for evaluation of fetal abnormalities, which is insufficient by conventional molecular approaches such as karyotyping and chromosomal microarray analysis (CMA), including NIHF (Sparks et al, 2020;Quinn et al, 2021).…”

“…Fotiou et al identified 10 PIEZO1 mutations in six families which cosegregate with the GLD phenotype. The affected individuals suffer from in utero demise, complete resolution after birth, the reappearance of lymphoedema in peripheries at early childhood, or recurrent facial cellulitis (Quinn et al, 2021).…”

“…Lymphatic disorders play an important part in the etiology of NIHF and comprise 15% of NIHF (Bellini et al, 2015). Based on strong and emerging evidence genes, the genetic variants associated with lymphatic malformations account for approximately 5.1% of NIHF, including FLT4, CCBE1, ADAMITS3, PIEZO1, EPHB4, SOX18, and FOXC2 (Quinn et al, 2021).…”

“…Yet this is not always the case, such as in lymphatic disorders. In those circumstances, WES is considered a potential technique to aid in the systematic evaluation of unexplained NIHF cases (Sparks et al, 2020;Quinn et al, 2021).…”

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

“…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 . Single-gene causes of NIHF are associated with significant risks of perinatal death or neurodevelopmental sequelae 2 .…”