ESPE Abstracts

Background: Idiopathic hypogonadotropic hypogonadism (IHH) is a congenital heterogeneous disorder characterized by a deficiency of gonadotropin-releasing hormone. IHH can be categorised as IHH with anosmia/hyposmia (Kallmann syndrome: KS) or as normosmic (n)IHH. More than 25 genes have been identified in IHH. Nevertheless, patients with IHH are genetically diagnosed in only less than 50%.

Objective: The objective of this study is to confirm the application of genetic diagnosis of IHH by targeted next-generation sequencing and to gain a greater understanding of the frequency of causative genes in Japanese IHH and their phenotype-genotype correlation.

Method: We developed a custom AmpliSeq panel of the coding sequences of 48 genes, of which 26 were causative genes of IHH and the remaining 22 genes were selected based on the protein-protein interaction network for IHH causative genes. These genes were sequenced in 23 patients with IHH from 21 unrelated Japanese families using the Ion PGM system. If a mutation was not detected and we had their parents’ DNA, trio sequencing was performed with the Illumina MiSeq instrument using TruSight One panel of 4813 genes that are involved in known Mendelian genetic disorders.

Results: Of the 23 patients, 17 had KS and 6 had nIHH. Molecular defects in ANOS1, CHD7, FGFR1, PROKR2 and TACR3 were identified in 11 patients from 9 families (43%, 9/21 pedigrees). Additionally, rare SNVs in CHD7, WDR11, and HS6ST1 were detected in 3 unrelated patients; however, we were unable to determine if they were pathogenic. Some patients with the CHD7 mutation had a cleft lip and/or plate and deafness.

Conclusion: Certain phenotype-genotype correlations were identified here, but they were not enough. It was thought that targeted next-generation sequencing was useful because it was difficult to determine the causative gene in a patient with IHH from only clinical features.