Hereditary Anemias as a Monogenic Etiology for Nonimmune Hydrops Fetalis

Hereditary anemias are a cause of nonimmune hydrops fetalis (NIHF). Our objective was to review the spectrum of hereditary anemia genes in NIHF diagnosed by exome sequencing (ES).

We performed a systematic review of ES studies in NIHF from January 1, 2000 to August 1, 2024 with emphasis on genes causing fetal anemia as a primary phenotype.

Forty-one ES studies with 207 genetically diagnosed NIHF cases met our inclusion criteria; 6 cases within 6 studies involved NIHF and hereditary anemia. Among the six cases, five had definitive diagnosis or likely diagnosis supported by pathogenic or likely pathogenic variants, while one case harbored only variants of uncertain significance and was classified as a possible diagnosis. The six different hereditary anemia genes included SEC23B, SPTA1, KLF1, RPL11, UNC13D, and RFWD3.

Overall, ES confirmed the etiology of hereditary anemia in 2.4% (5/207) of genetically diagnosed NIHF cases. Hereditary anemias, therefore, represent a distinct and clinically relevant subset of ES-diagnosed NIHF cases. ES should be considered first line in fetuses with NIHF, as common non-genetic causes such as fetomaternal hemorrhage, infectious etiologies, and alloimmunization are excluded. It is also indicated when fetal anemia is suspected, particularly in the setting of elevated MCA Dopplers with a negative evaluation for common hemoglobinopathies and nongenetic etiologies.