ESPE Abstracts

Background: Approximately one-third of the central precocious puberty (CPP) cases have familial transitions. Although more than 30 genes related to puberty have been reported to date, only a few (KISS1, KISS1R, MKRN3, DLK1 and PROKR2) were associated with CPP. This study aims to reveal the associated sequence variants of MKRN3 and DLK1 genes in cases with familial CPP and their etiology.

Method: This study includes 18 cases (16F, 2M) from different families, whose past medical history, physical examination, laboratory and follow-up records were evaluated. SDS calculation was performed according to national standards; bone-age (BA) was assessed by Greuclich-Pyle-method, and predicted adult height (PAH) was calculated according to Bayley-Pinneau-method. Family pedigrees were drawn for each case, and informed consents from all families were obtained before genetic testing. Sanger sequencing was performed in regions coding MKRN3(NM_005664.3) and DLK1(NM_003836.6). Segregation analyses were performed in families with pathogenic variants.

Results: The mean onset of pubertal age was 7.3 years (6.38-7.58) in females; 6.7 and 8.8 years in two males. The mean birth weight SDS was -0.6 (-1.3-0.9). At presentation, height and BMI SDS were 0.3 (-1.2-2.6) and -0.5 (-1.1-3.2) respectively. The mean BA was 8.8 years (7.8-10.5), and chronological age-BA difference was 3 years (1.6-4.9). Mean PAH was 156.7cm (-0.78 SDS) (147-171.6) in females;167.9 and 181.7cm in males. The mean target height SDS was -0.7 (-2.18 and -0.1) in females; -0.7 and 0.32 in males. Cranial-pituitary MRI of all cases was normal. Fifteen cases received GnRHa. Two different novel heterozygous variants in the DLK1 gene in two different families and a mutation in the MRKN3 gene in one case were detected. The first variant of DLK1 gene was c.357C>G(p.Tyr119Ter) in exon 4, and the second variant was c.67+78C>T in intron1. Segregation-analyses of these families had shown a paternal origin for the variants. The heterozygous variant in MRKN3 gene was c.982C>T(p.Arg328Cys, which is also paternally derived.

Conclusions: Although more frequent in literature, mutation in MKRN3 gene was detected only in one case in our study. Two-variants in the DLK1 gene were found to be compatible with the paternal imprinted gene model. In-silico analysis predicted that the first would lead to clipping error and the second to protein truncation. Transcription level study was planned for the clipping region change in the intronic region. We suggest that performing WES analysis in cases without pathogenic variant may help to explain the new genes and their relationships in familial CPP.