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, to allow accurate and timely management of delayed puberty patients. Design: Retrospective study Methods: Patients presenting with delayed puberty to UK Paediatric services, 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 rare, 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 diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only 3 patients. Fifteen predicted deleterious 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 been previously diagnosed as SLDP. Conclusion:This study supports the use of targeted exome sequencing in the 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.

Phenotypic spectrum of patients with mutations in CHD7: clinical implications of endocrinological findings

“…Genetic analysis of CHD7 contributes to the diagnosis of CHARGE syndrome and has expanded the phenotypic spectrum of CHD7 variants in individuals with lacking the full clinical features of CHARGE syndrome. CHD7 variants have been identified in normosmic isolated hypogonadotropic hypogonadism (nIHH), Kallmann syndrome (KS), self-limited delayed puberty, as well as CHARGE syndrome ( 3 , 4 , 5 , 6 , 7 ).…”

Combined omic analyses reveal novel loss-of-function NLGN3 variants in GnRH deficiency and autism

“…To validate the relevance of the top 20 genes in GD pathogenesis, the presence of potentially deleterious variants for each gene was interrogated in exomes from our cohort of GD patients (n = 47) (20). A male patient (Case 1) with partial GD (with puberty that had initiated and then arrested (21)) and ASD traits was found to carry a predicted loss-of-function (LoF) variant in the X-linked NLGN3 gene (Gene ID 5441; Figure 5A ).…”

Genetics of pubertal delay

“…68 The identification of the genetic basis of self-limited DP has been accelerated by the use of next-generation sequencing technology, 71 although in a recent cohort review only 24% of cases with self-limited DP who underwent whole-exome sequencing had likely causal variants identified. 72 To date, 14 genes have been identified as contributing to self-limited DP, including those identified in relatives of CHH probands and others identified from large cohorts of familial self-limited DP which have been T A B L E 1 Syndromic associations with congenital hypogonadotropic hypogonadism (CHH) or Kallmann syndrome (KS); Adapted from Howard 49…”

“…These genes code for neurokinin B and its receptor, an important element of the KNDy neuronal complex which controls GnRH pulsatility. 85 While heterozygous variants in TAC3/ TACR3 have been identified in self-limited DP patients using WES, 68,72 they have not been tested in vitro or in vivo for pathogenicity.…”

“…Additionally, heterozygous mutations of GNRHR have been identified in patients who manifest only with self-limited DP. 67,72 Interestingly, a partial loss-of-function mutation has been described in two brothers, one of whom had selflimited DP followed by normal endocrine profiles and fertility in adult life, while the other required testosterone replacement on into adult life consistent with a diagnosis of CHH. 86 Epigenetic mechanisms have been implicated in the regulation of the timing of puberty.…”