Primary ovarian insufficiency due to homozygous variants in the homeobox transcription factor NOBOX.

purposePrimary ovarian insufficiency (POI) is characterized by the loss of normal ovarian function and depletion of the ovarian reserve before the age of 40. Approximately 4-30% of reported POI cases are familial, indicating a genetic cause. The Newborn Ovary Homeobox (NOBOX) gene, an oocyte-specific transcription factor, plays an essential role in ovarian development and oogenesis in vertebrates. Pathogenic variants in the NOBOX gene are reported to cause autosomal dominant premature ovarian failure (OMIM 610934).

methodsWhole-exome sequencing (WES) was performed in a consanguineous family with two sisters affected by non-syndromic POI, and a familial history of ovarian anomalies and infertility. All exons of both sisters were sequenced by WES, and the segregation was confirmed by Sanger sequencing.

resultsHere, we identified a pathogenic homozygous missense variant (c.1048G > T, p.V350L) in the homeobox domain of NOBOX in the two sisters. The mother a confirmed carrier of the variant, currently aged 43, had her last child at the age of 40 and continues to have regular menstruation cycles.

conclusionThis data, together with other recent studies, indicates that POI due to variants in the NOBOX gene may be an autosomal recessive form of female infertility rather than an autosomal dominant condition. These findings support the reclassification of NOBOX-related POI as an autosomal recessive disorder and highlight the need for systematic genetic screening of NOBOX in patients with POI and their families.