A system‐based approach to the genetic etiologies of non‐immune hydrops fetalis

Abstract

A wide spectrum of genetic causes may lead to nonimmune hydrops fetalis (NIHF), and a thorough phenotypic and genetic evaluation are essential to determine the underlying etiology, optimally manage these pregnancies, and inform discussions about anticipated prognosis. In this review, we outline the known genetic etiologies of NIHF by fetal organ system affected, and provide a systematic approach to the evaluation of NIHF. Some of the underlying genetic disorders are associated with characteristic phenotypic features that may be seen on prenatal ultrasound, such as hepatomegaly with lysosomal storage disorders, hyperechoic kidneys with congenital nephrosis, or pulmonary valve stenosis with RASopathies. However, this is not always the case, and the approach to evaluation must include prenatal ultrasound findings as well as genetic testing and many other factors. Genetic testing that has been utilized for NIHF ranges from standard chromosomal microarray or karyotype to gene panels and broad approaches such as whole exome sequencing. Family and obstetric history, as well as pathology examination, can yield additional clues that are helpful in establishing a diagnosis. A systematic approach to evaluation can guide a more targeted approach to genetic evaluation, diagnosis, and management of NIHF.

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

“…Although the current definition of NIHF (as defined by the Society for Maternal-Fetal Medicine) specifies at least two pathologic fluid collections, this definition is poorly supported; genetic disorders can be manifested by only one abnormal fluid collection, and the types of abnormal fluid collections may change during gestation. 8,[12][13][14]23,26,27 A nondiagnostic karyotype analysis or chromosomal microarray analysis was required for eligibility in the study. Cases in which concurrent fetal structural anomalies had been present in the index pregnancy with NIHF were eligible for inclusion, as were cases of ongoing pregnancy, stillbirth, termination, live birth, and infant death.…”

“…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.…”

“…Some genetic disorders underlying NIHF portend mild long-term outcomes, whereas others are lethal despite treatment. 8,[12][13][14][15][16][17][18][19][20][21][22][23][24] An accurate diagnosis enables focused prenatal management and early, directed neonatal care to improve outcomes for this severe condition. The aims of this study were to establish the diagnostic yield of exome sequencing for single-gene disorders in unexplained NIHF and to describe the spectrum of underlying disorders.…”

Prenatal delineation of a distinct lethal fetal syndrome caused by a homozygous truncating KIDINS220 variant

“…Increased nuchal translucency and hydrops fetalis are additional novel features of KIDINS220 ‐related disorders that we are reporting. Both genetic disorders causing fetal akinesia and structural abnormalities of the cardiovascular system are responsible for as many as 50% of cases of early onset hydrops with poor prognosis, and a mortality rate close to 100% (Chen, 2012; Laterre, Bernard, Vikkula, & Sznajer, 2018; Mardy, Chetty, Norton, & Sparks, 2019; Yurdakök, 2014). These findings suggest that KIDINS220 to be considered in the differential diagnosis of fetal hydrops associated with both structural cardiac defects and congenital contractures.…”

Ultrasound examination: The key to maximising the benefits of advances in molecular diagnostic technologies

“…Hydrops is frequently associated with both skeletal dysplasias and arthrogryposis syndromes, and the review by Mardy et al expands on this to outline the known genetic aetiologies by fetal organ system to provide a systematic approach to the evaluation of non‐immune hydrops fetalis. They too highlight the need for careful evaluation of the family and obstetric histories, pathological examination, and the value of broad approaches to molecular diagnosis such as exome sequencing …”