Abstract Purpose Empty follicle syndrome (EFS) is a condition in which no oocyte is retrieved from mature follicles after proper ovarian stimulation in an in vitro fertilization (IVF) procedure. Genetic evidence accumulates for the etiology of recurrent EFS even with improved medical treatment which had avoided the pharmacological or iatrogenic problems. Here, this study investigated the genetic cause of recurrent EFS in a family with two infertile sisters. Methods In this work, we present two infertile sisters in a family with recurrent EFS after three cycles of standard ovarian stimulation with hCG and/or GnRHa therapy. We performed whole-exome sequencing and targeted sequencing in the core members of this family, and further bioinformatics analysis to identify pathogenesis of gene. Results We identified compound heterozygous variants, c.161_165del (p.54fs) and c.1166_1173del (p.389fs), on zona pellucida glycoprotein 1 (ZP1) gene, which were shared with two infertile sisters. Cosegregation tests on the affected and unaffected members of this family confirmed that the allelic mutants were transmitted from either parent. Conclusions This EFS phenotype was distinct from the previously reported disruption of zona pellucida due to homozygous ZP1 defects. We thus propose that the specific mutations in ZP1 gene may render a causality for the recurrent EFS.

Compound heterozygous ZP1 mutations cause empty follicle syndrome in infertile sisters