Genetic analysis of hyperemesis gravidarum reveals association with intracellular calcium release channel (RYR2)
Hyperemesis Gravidarum (HG), severe nausea/vomiting in pregnancy (NVP), can cause poor maternal/fetal outcomes. Genetic predisposition suggests the genetic component is essential in discovering an etiology. We performed whole-exome sequencing of 5 families followed by analysis of variants in 584 cases/431 controls. Variants in RYR2 segregated with disease in 2 families. The novel variant L3277R was not found in any case/control. The rare variant, G1886S was more common in cases (p = 0.046) and extreme cases (p = 0.023). Replication of G1886S using Norwegian/Australian data was supportive. Common variants rs790899 and rs1891246 were significantly associated with HG and weight loss. Copy-number analysis revealed a deletion in a patient. RYR2 encodes an intracellular calcium release channel involved in vomiting, cyclic-vomiting syndrome, and is a thyroid hormone target gene. Additionally, RYR2 is a downstream drug target of Inderal, used to treat HG and CVS. Thus, herein we provide genetic evidence for a pathway and therapy for HG.
Fejzo, M. S., Myhre, R., Colodro-Conde, L., MacGibbon, K. W., Sinsheimer, J. S., Reddy, M. V. P. L., . . . Mullin, P. M. (2017). Genetic analysis of hyperemesis gravidarum reveals association with intracellular calcium release channel (RYR2). Molecular and Cellular Endocrinology, 439, 308-316. doi:10.1016/j.mce.2016.09.017