The use of whole-exome sequencing to identify known and novel monogenic etiologies in patients with central precocious puberty
Date
2023
DOI
Authors
Barrera-Zevallos, Paola Alexandra
Version
OA Version
Citation
Abstract
BACKGROUND: Beyond environmental, socioeconomic, or nutritional causes, genetic etiologies are still being uncovered as contributors to deviations from average pubertal timing determined by population studies. Central precocious puberty is a pubertal disorder that is characterized by reaching certain pubertal markers before the appropriate sex-specific age the markers should be reached at. Although there are many contributing components to this disorder, familial and twin studies strengthen the argument that genetics play a crucial role in understanding the mechanisms behind these pubertal timing deviations. Currently, there are five known genetic variants that have been linked to CPP: Makorin Ring Finger Protein 3 (MKRN3), Delta-like noncanonical Notch ligand 1 (DLK1), Prokineticin receptor 2 (PROKR2), Kisspeptin (KISS1), and its receptor (KISS1R). Any other genetic etiologies of CPP remain to be elucidated, especially when contrasted to the more than 50 genes identified with another pubertal timing disorder, hypogonadotropic hypogonadism (e.g. delayed puberty).
OBJECTIVE: CPP was previously described to be mostly ‘idiopathic’ unless a pathologic organic cause was found to be contributing to the disorder. With the growing familial studies that aid in identifying the known variants as contributors to a patients’ CPP, one
must wonder whether there are any unknown variants in other suspected genes that could also contribute to CPP. It is hypothesized that children with a previous diagnosis of ‘idiopathic’ CPP could potentially have an uncovered monogenic etiology for their pubertal disorder. With an emphasis on family history, this study aims to understand the inheritance patterns that influence any genetic etiologies for the improvement of familial screening, as well as to integrate any findings to a patient’s medical record.
METHODS: The recruitment of participants was based on Boston Children’s Hospital Endocrine Clinic and satellite locations. Participants that were selected for recruitment met the inclusion criteria of a physician confirmed CPP diagnosis and would subsequently perform a buccal swab collection for whole-exome sequencing analysis (WES). The WES data would then be uploaded to AI genomic platform called Emedgene that allowed for further analysis into variant information including allele frequency, related diseases, and familial zygosity patterns.
RESULTS: There are 22 returned WES data for analysis from patients. A frameshift (p.Met268ValfsTer23) and missense mutation (p.Arg345Cys ) affecting the gene MKRN3 were identified in two female patients in the cohort respectively. The protein areas the mutations were found to be affecting are causative to MKRN3 dysfunction based on previous studies.
CONCLUSION: Previously described cases of idiopathic CPP are now being reported as cases with known or novel monogenic causes. With the growing amount of genetic variants that cause CPP being uncovered, in addition to the inheritance imprinting nature of these genes, there is an emphasis on expanding familial genetic studies to uncover the enigma behind the mechanism of pubertal regulation. Finally, the addition of clinical confirmation of genetic variants allows for research to become a part of a patient’s medical record, thus further innovating pediatric precision medicine.