LAUSR

INTRODUCTION Idiopathic Hypogonadotropic hypogonadism (IHH) is caused by dysfunction of the hypothalamic-pituitary-gonadal axis. DLG2 was recently implicated as a gene associated with delayed puberty and which may also contribute to IHH. The confirmation of the candidate puberty genes in independent IHH cohorts has become crucial due to the lack proper genotype phenotype segregations in reported pedigrees. Therefore, we aimed to screen DLG2 in patients variants in a large cohort of IHH patients. METHODS The present study included a total of 336 IHH patients from 290 independent families. The coding and flanking regions of the DLG2 were screened for potentially important variants in the WES data. Candidate variants were evaluated in the gnomAD and GME databases according to their allele frequencies, and only those with a frequency <0.0001 were considered rare. Detected variants were classified according to the ACMG/AMP criteria. RESULTS We found one homozygous and two heterozygous missense variants in three independent pedigrees. Identified variants were found extremely rare or not reported in gnomAD. Two variants were categorized as "uncertain significance" the other one was "likely pathogenic" according to the ACMG criteria. All patients were normosmic, and in two of the three families there were no causal variants in other IHH-related genes. CONCLUSION We detected three rare sequencing variants in DLG2 in five patients with IHH or delayed puberty in a large IHH cohort. Our results support the contention that the DLG2 mutations are associated with IHH in human puberty.