ESPE Abstracts

Background: The major genetic causes of CPP are the paternally inherited Makorin RING-finger protein 3 (MKRN3) and Delta-like homolog 1 (DLK1) deficiencies. Exceedingly rare patients with CPP carry variants in kisspeptin system. The CPP genes are also associated with the age at menarche in the population as demonstrated by genome-wide association studies (GWAS). Nuclear Receptor Coactivator 5 (NCOA5) is a coregulator for the alpha and beta estrogen receptors and is associated with the age at menarche by GWAS.

Objectives: To identify novel genetic causes of CPP.

Population and Methods: Whole genome sequencing (WGS) of 14 family trios and one additional proband affected with familial CPP, demonstrating maternal (10 pedigrees) or paternal / recessive inheritance pattern (5 pedigrees), was performed. In additional 38 probands (13 girls with maternally inherited CPP, 5 sporadic boys, 20 sporadic girls with CPP onset before 7 years) whole exome sequencing (WES) was performed. Coding regions of 398 genes reported to be associated with age at menarche by GWAS were analysed for rare variants (MAF<0.2%) by targeted approach. Genetic variants with coverage >10x were retained and analysed with Variant Studio 3.0 software. Identified candidate variants and their family segregation were verified by Sanger sequencing. Coding variants in the MKRN3 gene were pre-screened and excluded by Sanger sequencing in all probands without obvious dominant maternal inheritance.

Results: In a pedigree with maternal inheritance a rare missense variant p.R70W (gnomAD allele frequency 1.59e-5) in silico predicted to be pathogenic (CADD score 26.6) in NCOA5 gene was identified by WGS. The variant segregated with CPP or early puberty in the mother (menarche at 10 years), and two sisters. The proband carrier had telarche at the age of 6 years with markedly advanced bone age (+3.5 SD), tall stature (+3.3 SD) and increased basal and GnRH-stimulated luteinizing hormone (LH). Her older sister had telarche, pubertal LH levels, growth acceleration and bone age advancement (+1.65 SD) at the age of 8 years. No other NCOA5 coding variants and no DLK1 variants were identified in the rest of the cohort.

Conclusions: A rare variant of unknown significance in a gene implicated in the regulation of estrogene receptors, NCOA5, was identified in a pedigree with maternally inherited CPP. The implication of identified variant on NCOA5 function and CPP phenotype remains to be determined. Variants in DLK1 gene were not a common cause of CPP in our cohort.