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Background: Loss of imprinting has been implicated in the pathogenesis of several human diseases. Monogenic causes of central precocious puberty (CPP) were identified in families with loss-of-function mutations affecting mainly the coding region of two paternally expressed imprinted genes: Makorin ring finger 3 (MKRN3) and Delta-like 1 homolog (DLK1). The role of imprinting defects involving these two genes in CPP has not been described so far. Objective: To investigate the methylation status at primary differentially methylated regions (DMR) of MKRN3 and DLK1 in a cohort of children with idiopathic CPP. Patients and methods: One-hundred and twenty CPP patients (112 sporadic, 8 familial; 115 females, 5 males) were selected for analysis. Leukocyte DNA was obtained from all patients. MKRN3 and DLK1 pathogenic allelic variants were first excluded by DNA sequencing analysis. Bisulfite treatment followed by Allele-Specific Methylated Multiplex Real-Time Quantitative PCR was performed with leukocyte DNA, analyzing separately the methylation index (MI) of MKRN3:TSS-DMR and DLK1/MEG3:IG-DMR for each patient. The MI results were compared with controls with normal pubertal development. Results: Mean age at puberty onset was 5.8 ±1.9yr for girls and 7.2 ±2.6yr for boys. Hypomethylation at DLK1/MEG3:IG-DMR was identified in 3 patients (I, II and III) with sporadic CPP: MI 10%, 16% and 11%, respectively. Interestingly, cases II and III were both girls who had been firstly referred to pediatric endocrinology for presenting precocious menarche; while case I was a boy who had been referred for presenting mild growth retardation, and developed CPP during monitoring. In addition, during follow-up, other clinical findings were noticed: being born small for gestational age, prominent forehead, small hands/feet, overweight/obesity and early onset type 2 diabetes in case III. Additional genetic investigation included SNP array in cases I and II, identifying a maternal uniparental disomy at chromosome 14 (upd(14)mat). Meanwhile, case III had normal genomic microarray and microsatellites analysis, excluding copy number variants and upd(14)mat, and indicating a mechanism of epimutation at DLK1/MEG3:IG-DMR. Uniparental disomy and epimutation are molecular mechanisms associated with the imprinting disorder known as Temple syndrome. In the remaining cases, mean MI for DLK1/MEG3:IG-DMR was 49±2%. In all cases, mean MI for MKRN3:TSS-DMR was 49±6%. There were no significant correlations between age at puberty onset and MI for MKRN3 (p=0.69) and DLK1(p=0.45). Conclusion: There was no leukocyte DNA methylation defect at MKRN3 imprinting control region in the idiopathic CPP cohort. DLK1/MEG3:IG-DMR hypomethylation was identified in 3 patients with CPP and additional findings of Temple syndrome, indicating that loss of effective imprinting of DLK1 locus is a mechanism leading to CPP.

journal of the endocrine society

SUN-090 Investigation of Imprinting Defects in MKRN3 and DLK1 in Children with Idiopathic Central Precocious Puberty Through Specific DNA Methylation Analysis