Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty

Abstract

Context: Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents. Objective: To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients. Design: Retrospective study. Methods: Patients presenting with delayed puberty to UK Paediatric serv ices, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed. Results: Forty-six patients were included, 54% with a final clinical dia gnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted d eleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had bee n previously diagnosed as SLDP. Conclusion: This study supports the use of targeted exome sequencing in th e clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately 2021 The authors Published by Bioscientifica Ltd Printed in Great Britain.