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.