Study Details Prevalence of Genetic Variants in Central Precocious Puberty

Results of a recent study provide insight into the prevalence of rare sequence variants among the MKRN3, DLK1, KISS1, and KISS1R genes in children with CPP.

A recent study by a team of European investigators is underlining the importance of an individualized approach in the management and treatment of central precocious puberty (CPP).

A translational study examining pathogenic and low-frequency variants in children with CPP, results of the study detail the incidence of rare sequence variants among MKRN3, DLK1, KISS1, and KISS1R genes in a cohort of children, including girls and boys, with CPP.

“The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP,” wrote investigators in their conclusion.

A rare pubertal disorder with an apparent knowledge gap related to genetic determinants, the current study was designed by a team of investigators based in Greece and Cyprus with an interest in describing rare sequence variants among the MKRN3, DLK1, KISS1, and KISS1R genes.

The study population included in the analysis was a cohort of children, including 54 girls and 2 boys with CPP, referred for genetic investigation to the Department of Molecular Genetics, Function, and Therapy at the Cyprus Institute of Neurology and Genetics. All children included in the study met the criteria for CPP diagnosis, which was defined as presenting with breast development Tanner stage 2 before the age of 8 years in girls and presenting with testicular enlargement more than 4 ml in volume measured with Prader orchidometer before the age of 9 years in boys.

All children who were found negative for the MKRN3 gene underwent further investigation through whole exome sequencing. Results of whole exome sequencing among these children was compared against an in-house cohort of Cypriot children with CPP. Investigators pointed out the identified rare variants were initially examined by in silico computational algorithms and subsequently comfier with Sanger sequencing. Investigators also pointed out a genetic network for the MKRN3 gene, which replicated a holistic regulatory depiction of the crosstalk between MKRN3 and other genes, was designed for the purpose of analysis.

Upon analysis, 3 previously described pathogenic variants of the MKRN3 gene were located in the coding region of the gene were identified in 12 girls with CPP. Specific mutations included the missense p.Gly312Asp was in 7 index girls, the frameshift p.Met268ValfsTer23 in 4 index girls,

and the nonsense p.Glu298Ter in 1 index girl with CPP. Investigators noted the most common pathogenic MKRN3 variant p.Gly312Asp was observed exclusively among patients within the Cypriot CPP cohort, which indicates a founder effect phenomenon.

In the cohort of 44 children who underwent whole exome sequencing, investigators identified 9 rare DLK1 variants among 11 girls, a pair of rare KISS1 variants among 6 girls, and a pair of rare MAGEL2 variants among 5 girls. Investigators also pointed out rs10407968 variant of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP.

“We confirmed the key role of the imprinted MKRN3 gene as the most common cause of monogenic CPP in the Cyprus cohort. The newly described p.Gly312Asp missense loss-of-function pathogenic variant was identified as the most prevalent among the tested Cypriot CPP cohort. This could be most likely due to the founder effect, a frequent phenomenon in the Cypriot population,” wrote investigators.

This study, “Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty,” was published in Pediatric Endocrinology.