Delaney A, Burkholder AB, Lavender CA, et al. - Experts aspired to explore whether the burden of rare sequence variants (RSVs) in isolated hypogonadotropic hypogonadism (IHH)-related genes is higher in women with hypothalamic amenorrhea (HA) than controls. This investigation was carried out at secondary referral centers. Participants in the study were women with HA (n = 106) and control women (ClinSeq study; n = 468). Exome sequencing was done in all patients and controls. Using rare variant burden and association tests, the frequency of RSVs in 53 IHH-associated genes was determined. Compared with controls, RSVs were overrepresented in women with HA. According to findings, women with HA were enriched for RSVs in genes that cause IHH, indicating that variation of the genes related to GnRH neuronal ontogeny and function can be a major determinant of individual susceptibility to developing HA in the face of diet, exercise and/or stress.