ESPE Abstracts (2018) 89 P-P1-204

Whole-exome Sequencing Identifies Novel Pathogenic Variants in Korean Families with Central Precocious Puberty

Hae Sang Lee & Jin Soon Hwang

Ajou University Hospital, Suwon, Republic of Korea

Objective: Central precocious puberty (CPP) is characterized by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Early activation of hypothalamic-gonadal axis is influenced by both environmental and genetic factors. Especially, genetic factors have critical role of pubertal progression, but mutations associated with CPP have only been discovered in three genes: KISS1, KISS1R, and MKRN3. The aim of this study was to identify novel, potentially pathogenic variants from a whole-exome sequencing study in Korean families with CPP.

Methods: Whole-exome sequencing was performed in 52 members of 14 families with CPP. Familial CPP was defines by the presence of more than one member of a family with a history of precocious puberty. Data analysis selected only very rare variants (MAF<0.1%). Rare stop-gain, stop-loss, splice-site variants, frameshift, in-frame insertions/deletions were considered as the most candidate variants. Additionally, non-synonymous missense variants with three or more deleterious predictions (SIFT, Polyphen, LRT and Mutation Taster) were further considered. Ingenuity Pathway Analysis (IPA; Qiagen; was used to detect significant enrichment for biological functions and molecular networks. Exome sequencing results for prioritized variants were validated using Sanger sequencing. We also measured the messenger RNA (mRNA) expression of the candidate genes in the hypothalamus of mice at different ages.

Results: The sequencing achieved good coverage of the target regions (99% average total coverage at 1X and 95% average total coverage at 20X) with enough depth (>200X). After filtering of the exome data, a total of 33 candidate genes were identified. These consist of 2 stop-gain, 7 frameshift, 7 missense, 6 splice-site variant, and 11 in-frame insertions/deletions. Among these genes, AR, BMP6, EAP1, SLIT2 and NCOR1 were prioritized. Especially, novel in-frame deletion (p. Gln115del) in EAP1 was the most interesting variants for CPP and was identified in 12 out of 14 families. Both sexes were affected. The mRNA Levels of EAP1 declined just before puberty, so levels of EAP1 in prepubertal mice were significantly higher compared to those in pubertal mice.

Conclusions: We identified new potential genes that could play a role in pubertal progression. Our findings broaden the genetic background of CPP and EAP1 can be a pathogenic gene for CPP.

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