Performance of exome sequencing in premature ovarian insufficiency: a systematic review and meta-analysis

Premature ovarian insufficiency (POI), one of the major and intractable causes of female infertility, affects 1.9-3.5% of the population. An increasing number of genes has found to be involved in the pathogenesis of POI.

Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and CINAHL were searched from inception until May 2024. Studies were examined to assess the positive rate of monogenic pathogenic (P) and likely pathogenic (LP) variants, classified according to the American College of Medical Genetics and Genomics (ACMG) criteria, of exome sequencing (ES) testing in patients with spontaneous POI. Meta-analysis of proportions was employed using a random-effects model based on data extracted from included studies. Quality assessment of the included studies was performed using modified Standards for Reporting of Diagnostic Accuracy criteria (STARD).

Eleven studies were included consisting of 1740 individuals with spontaneous POI. The qualities of included studies were assessed to be moderate to high according to the modified STARD. The overall positive rate of monogenic P/LP variants in ES testing on women with POI was 31% (95%CI 18-44%; I² = 89%). The yield was similar in spontaneous POI with clinical phenotype of primary amenorrhoea (PA) (38%, 95%CI, 21%-54%; I² = 73%; 207 participants, 8 studies) and those with secondary amenorrhoea (SA) (33%, 95%CI, 14%-53%; I² = 91%; 1077 participants, 8 studies). Meanwhile, the overall diagnostic yield (rule out cases with monoallelic P/LP variant in recessive genes or variants on genes without clear link to the phenotype of POI) of ES testing on individuals of POI was 21% (95%CI 12-31%; I² = 87%). The yield was significant higher in spontaneous POI with PA (33%, 95%CI, 16%-49%; I² = 72%; 207 participants, 8 studies) compared with those with SA (18%, 95%CI, 5%-32%; I² = 79%; 1077 participants, 8 studies). Linear regression asymmetry test showed no significant quantification of bias (P≥0.05).

This meta-analysis provided evidence on the overall positive rate of monogenic P/LP variants and diagnostic yield of ES testing in spontaneous POI. Our result supports the inclusion of spontaneous POI in the current recommendation of ES to dissect the further genetic etiology.

This review was registered in PROSPERO (CRD42024548553).