Context: Primary ovarian insufficiency (POI), or premature ovarian failure, results from ovarian follicle depletion with a consequent elevation of FSH levels before age 40 years. We identified a family in which 9 women in 3 consecutive generations developed menopause at approximately age 30 years. We hypothesized a genetic cause with a dominant mode of inheritance.
Design: This was a family-based genetic study and a replicate group of women with POI.
Setting: The study was conducted at an academic medical center.
Patients: Seven affected women and an obligate carrier and 7 unaffected family members were genotyped. The genes of interest were also sequenced in 38 unrelated women with POI.
Intervention: The DNA from 7 family members was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of additional family members and unrelated women with POI were determined using Sanger sequencing.
Main outcome measure: A high-impact, deleterious variant that segregated appropriately with POI in the family was required.
Results: A heterozygous stop codon (Ser429X) was identified in the eukaryotic translation initiation factor 4E nuclear import factor 1 (eIF4ENIF1) in the proband and all affected women but not in the unaffected family members. The chance that such a high-impact, deleterious variant would segregate appropriately among the affected and unaffected relatives by chance is very low (P < .05). There were no additional mutations identified in eIF4ENIF1 or eIF4E in 38 unrelated women with POI.
Conclusion: Data demonstrate a new gene associated with dominantly inherited POI. These results highlight the importance of translation initiation factors and their regulators in ovarian function.