Diagnostic yield of clinical exome sequencing in congenital hypogonadotropic hypogonadism considering the degree of olfactory impairment

Introduction: Congenital hypogonadotropic hypogonadism (CHH) can present alone or in asso-ciation with anosmia or other congenital malformations. More than 30 genes have been identified as being involved in the pathogenesis of CHH with different patterns of inheritance, and the increasing availability of next generation sequencing (NGS) has increased the diagnostic yield.Methods: We analysed the diagnostic yield of NGS in patients with CHH using the clinical exome filtered with virtual panels. We also assessed whether designing panels based on the presence/absence of microsmia increased the diagnostic yield.Results: The use of a 34-gene virtual panel confirmed the diagnosis of CHH in 5 out of 9 patients (55%). In 2 out of 9 (22%), the findings were inconclusive. Applying the presence/absence of microsmia criterion to choose genes for analysis did not improve the diagnostic yield.Conclusions: The approach to the genetic study of patients with CHH varies depending on the resources of each healthcare facility, so the sensitivity of testing may vary substantially depen-ding on whether panels, clinical exome sequencing or whole exome sequencing (WES) are used. The analysis of every genes related to CHH regardless of the presence/absence of microsmia seems to be the best approach.(c) 2021 Asociacion Espanola de Pediatria. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

Automated summary

This study aimed to evaluate the diagnostic yield of NGS in patients with CHH and explore the analysis method of selecting genes based on microsmia. The results showed that the virtual panel method confirmed the diagnosis of CHH in 5 patients, while selecting genes based on microsmia did not improve the diagnostic yield. Therefore, analyzing all genes related to CHH may be the most effective approach.