P–534 A novel heterozygous mutation in the luteinizing hormone/choriogonadotropin receptor (LHCGR) gene in a patient with ‘genuine’ empty follicle syndrome
Authors: Sarikaya E , Topçu V , Ceylan A C , Yılmaz N 
Published: August 2021

Study question

Whether empty follicle syndrome (EFS) in a patient has a genetic basis.

Summary answer

Our findings would expand the mutational spectrum of LHCGR, in patients with GEFS

What is known already

The LHCGR gene (OMIM #52790) is located on chromosome 2p21 has 11 exons The LHCGRs present in gonadal cells; granulosa, theca and luteal cells in women and Leydig cells in menandplays a critical role in male sexual differentiation, female ovarian development and fertility (folliculogenesis, ovulation, corpus luteum formation and progesterone secretion)

Inactivating mutations in males can lead to Leydig cell hypoplasia, which causes disorders in sexual development (MIM #238 320). Phenotype of women is less severe and variable and has no effect on the secondary sex characteristics, but it could cause amenorrhoea and infertility Study design, size, duration: In the context of clinical genetics, Next Generation Sequencing libraries were prepared in line with the manufacturer’s orders using QIASeq™ Targeted DNA Custom Panel (Qiagen) targeting exons and 20 bp exon-intron boundaries of selected genes (AR, BMP15, CATSPER1, CFTR, CYP21A2, FSHB, FSHR, HESX1, LHB, LHCGR, NR5A1, POU1F1, SRY, ZP1). The variant detected in NGS analysis was further confirmed using Sanger sequencing (MiSeq, Illumina, San Diego, CA).

Participants/materials, setting, methods

A 27 years old Turkish women with 6 year history of primary unexplained infertility underwent controlled ovarian hyperstimulation and IVF with an antagonist protocole in Ankara City Hospital. Although normal follicular development, E2 levels, and bioavailable β-hCG plasma levels, no oocytes or cumulus-corona complexes were retrieved by follicular aspiration.

Main results and the role of chance

A novel heterozygous mutation on Exon 5 of LHCGR (NM_000233.4):c.453C&gt;G (p.Phe151Leu). This variant has not been reported in GnomAD database and is a novel variant as per controlled from ClinVar and HGMD mutation databases

Also coagulation tests were done Patient was heterozygote for the prothrombin mutation (FXIII) and homozygote for MTHFR C677T mutation. The patient has normal pubertal development and female karyotype (46,XX). Gonadotropin and E2 levels were normal, nor any history of anosmia, primary amenorrhoea, polycystic ovaries, hyperandrogenism, systemic disorder, or neurologic defect.

According to ACMG 2015 and HGMD detected variant was classified as unknown clinical significance (VUS) variant In 22nd World Congress COGI in 2015 we have presented another recurrent GEFS case with compound heterozygous frameshift mutations in exon 5 and 11 of LHCGRgene(c.1764_1765insT) and (c.430G&gt;T, p.V144F) who developed premature ovarian failure at the end The different types of LHCGR mutations would lead to the different functional effects and clinical phenotypes in different ages; primary amenorrhea with high levels of LH, poor ovarian response (Poesidon group1), GEFS and secondary amenorrhea (premature ovarian failure) GEFS may be a gradual biological occurrence related to ovarian ageing. Long term follow up is important, since some clinical manifestations appear later in life.

Limitations, reasons for caution

LH resistance in females were always found due to their effected brothers and only 10 GEFS cases of 46, XX females with LHCGR gene defect reported in literature.

Patient was heterozygous for indicated mutation; therefore segregation study should be done in family members and in vitro studies should be performed.

Wider implications of the findings: Screening for mutations in the LHCGR gene in Poseidon group 1 and in patients GEFS especially the recurrent ones will provide valuable information and time for clinical management, corresponding treatment and give the opportunity of wise and cost effective counseling of patients about their future reproductive choices.

Trial registration number

it is a case report