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22Purpose 23 Empty follicle syndrome (EFS) is a condition in which no oocyte is retrieved from mature follicles 24 after proper ovarian stimulation in an in vitro fertilization (IVF) procedure. Genetic evidence 25 accumulates for the etiology of recurrent EFS even with improved medical treatment which had 26 avoided the pharmacological or iatrogenic problems. Here, this study investigated the genetic 27 cause of recurrent EFS in a family with two infertile sisters. 28 Methods 29In this work, we present two infertile sisters in a family with recurrent EFS after three cycles of 30 standard ovarian stimulation with hCG and/or GnRHa therapy. We performed whole-exome 31 sequencing and targeted sequencing in the core members of this family, and further 32 bioinformatics analysis to identify pathogenesis of gene. 33 Results 34We identified compound heterozygous variants, c.161_165del (p.54fs) and c.1166_1173del 35 (p.389fs), on zona pellucida glycoprotein 1 (ZP1) gene, which were shared with two infertile 36 sisters. Cosegregation tests on the affected and unaffected members of this family confirmed 37 that the allelic mutants were transmitted from either parent. 38 Conclusions 39 This EFS phenotype was distinct from the previously reported disruption of zona pellucida due to 40 homozygous ZP1 defects. We thus propose that the specific mutations in ZP1 gene may render a 41 causality for the recurrent EFS. 42 43 Key words 44 ZP1, in vitro fertilization, empty follicle syndrome 45 46 Dr. Ling Sun gained her MD in 1995 and her PhD in 2007. She is a 47 inhibition, this mutation could destroy the assembly of the zona pellucid (ZP) thus leading to 69 oocyte degeneration and EFS. However, the etiology research on EFS, especially those recurrent 70 ones, is far from completeness, therefore, the full spectrum of genes and mutations involved in 71EFS are still to be expanded. 72In this study, we identified compound heterozygous mutations of ZP1 gene (MIM#195000) from