[Genetic variants analysis of 17 female patients with idiopathic hypogonadotropic hypogonadism]

To analyze the clinical phenotype characteristics and genetic testing data of idiopathic hypogonadotropic hypogonadism (IHH) female patients, aiming to improve the understanding of genetic etiology and inheritance patterns among female patients.

This study recruited twenty-one female patients and their clinical data were collected and analyzed. Based on the olfaction function, the patients were divided into normosmic IHH group and Kallmann syndrome (KS) group. Whole exome sequencing and Sanger sequencing were performed to screen for underlying genetic etiology including genetic variants of known pathogenic genes and PLEXIN pathway genes. Alphafold2 was used for mutant protein structure prediction of PLXNA1 missense mutation.

Normosmic IHH patients and KS patients had no difference in baseline clinical data. Among the 21 recruited patients, 17 patients and their immediate family members' peripheral blood was collected for sequencing, and four patients were found carrying pathogenic variants involving FGFR1 and PROKR2, and the pathogenic variant carrying rate was 23.5%. The remaining 13 patients didn't obtain a specific genetic diagnosis. Two KS patients withoutknown pathogenic variants carried the same heterozygous variant PLXNA1: c.3401G>A but no other PLEXIN pathway gene variants. The missense mutation caused hydrophobicity change of the 1134 amino acid loci of PLXNA1. Four patients with family history carried relevant gene variants involving FGFR1, CHD7 and POLR3B. However, the genetic diagnosis of some patients wasn't reached because the pathogenicity of these variants only reached variants of unknown significance based on American College of Medical Genetics and Genomics (ACMG) guidelines and the genotype-phenotype co-segregation within family was inconsistent. Female IHH patients could only maintain secondary sex characteristics and artificial menstruation through hormone replacement treatment and gain fertility by gonadotropin ovulation sti-mulating therapy.

Female IHH patients have complex genetic etiology and polygenic inheri-tance mode. Both hereditary and sporadic patients may have various degrees of genetic inheritance risk. The missense variant PLXNA1: c.3401G>A might be a potential risk variant of KS.