Premature ovarian insufficiency (POI) is characterized by the loss or complete absence of ovarian activity in women under the age of 40. Clinical presentation of POI varies with phenotypic severity ranging from premature loss of menses to complete gonadal dysgenesis. POI is genetically heterogeneous with >100 causative gene variants identified thus far. The etiology of POI varies from syndromic, idiopathic, monogenic to autoimmune causes the condition. Genetic diagnoses are beneficial to those impacted by POI as it allows for improved clinical management and fertility preservation. Identifying novel variants in candidate POI genes, however, is insufficient to make clinical diagnoses. The impact of missense variants can be predicted using bioinformatic algorithms but computational approaches have limitations and can generate false positive and false negative predictions. Functional characterization of missense variants, is therefore imperative, particularly for genes lacking a well-established genotype:phenotype correlation. Here we used whole-exome sequencing (WES) to identify the first case of a homozygous missense variant in DIS3 (c.2320C > T; p.His774Tyr) a critical component of the RNA exosome in a POI patient. This adds to the previously described compound heterozygous patient. We perform the first functional characterization of a human POI-associated DIS3 variant. A slight defect in mitotic growth was caused by the variant in a Saccharomyces cerevisiae model. Transgenic rescue of Dis3 knockdown in Drosophila melanogaster with human DIS3 carrying the patient variant led to aberrant ovarian development and egg chamber degeneration. This supports a potential deleterious impact of the human c.2320C > T; p.His774Tyr variant.

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Case Reports | Journal Article

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Kline BL, Siddall NA, Wijaya F, Stuart CJ, Orlando L, Bakhshalizadeh S, Afkhami F, Bell KM, Jaillard S, Robevska G, ... Show all

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