ESPE Abstracts (2022) 95 P1-358

1The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; 2Aretaeio Hospital, Nicosia, Cyprus; 3Iliaktida Paediatric & Adolescent Medical Centre, Limassol, Cyprus; 4University of Nicosia Medical School, Nicosia, Cyprus; 5National and Kapodistrian University of Athens Medical School, Athens, Greece; 6Biomedical Research Foundation of the Academy of Athens, Athens, Greece; 7Archbishop Makarios III Hospital, Nicosia, Cyprus; 8Paedi Center for specialized Pediatrics, Nicosia, Cyprus

Background: Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height as well as psychological consequences. So far only a limited number of genetic determinants have been associated with the pathogenesis in children with CPP. In this original research, rare sequence variants in MKRN3, DLK1, KISS1, and KISS1R genes were investigated in patients with CPP.

Methods: Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the MKRN3 gene. All children (n = 44) negative for pathogenic variants with Sanger, underwent whole exome sequencing (WES) by Next Generation Sequencing (NGS). The frequencies and status of the newly identified novel and rare variants of the present study in genes known to be related with pubertal timing were compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were firstly examined by in silico computational algorithms and confirmed by Sanger. Moreover, a genetic network for the MKRN3 gene, mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes was created.

Results: Three previously described pathogenic MKRN3 variants were identified in 12 index girls with CPP, with one (P.Gly312Asp) being exclusively found among seven probands of the Cypriot CPP cohort and never reported before, indicative of a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the MKRN3. Among the 44 CPP patients submitted to WES, nine rare DLK1 variants were identified in 11 girls, two rare KISS1 variants in six girls, and two rare MAGEL2 variants in five girls. Interestingly, the frequent variant rs10407968 (P.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP.

Conclusion: The outcomes of the present study highlight the importance of the MKRN3-imprinted gene in the development of CPP and its key role in pubertal timing. Furthermore, they also emphasize the importance of an approach that aligns genetics and clinical aspects, which is essential for the management and treatment of CPP.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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