Inherited mutation of the luteinizing hormone/choriogonadotropin receptor ( LHCGR ) in empty follicle syndrome

Objective To test by genomic analysis whether empty follicle syndrome (EFS) in a family with two affected sisters has a genetic basis. Design Whole-exome sequencing in the context of clinical genetics. Setting University hospital. Patient(s) Two women (36 and 32 years old at the time of the study) with EFS. Intervention(s) Genetic counseling based on autosomal recessive inheritance. Main Outcome Measure(s) Discovery of a mutation in the LH/choriogonadotropin receptor ( LHCGR ) as the cause of EFS. Result(s) A novel missense mutation in LHCGR , p.N400S, was homozygous in sisters with EFS and/or infertility, but not in their unaffected siblings or parents. The mutation was not present in 500 ancestry-matched control subjects. Asparagine at residue 400 is highly conserved and its substitution by serine predicted to alter critical interactions that stabilize LHCGR. Conclusion(s) We describe a genetic basis for EFS and provide strong evidence for the existence of genuine EFS in some patients. A mutation impairing the function of LHCGR explains the lack of response of these patients to repeated administration of β-hCG.