Endocrine Abstracts

Background: The genetic causes of central precocious puberty (CPP) of clinical value identified to date are the paternally inherited Makorin RING-finger protein 3 (MKRN3) and Delta-like homolog 1 (DLK1) deficiencies. Given that CPP is typically maternally inherited, however, the molecular genetic background in the majority of CPP cases remains unknown. Using candidate gene approach focused on genes regulating GnRH secretion and action so far exceedingly rare patients with CPP were shown to carry mutations in kisspeptin system. KISS1 receptor gene (KISS1R) autosomal dominant heterozygous activating mutation p.(Arg386Pro) was reported previously in a girl with CPP by Teles MG et al.

Objectives: To identify genetic causes of maternally inherited CPP.

Population and methods: Whole genome sequencing of 9 family trios affected with CPP, demonstrating maternal inheritance pattern, was performed. A family trio analysis approach was utilized as a first tier analysis to generate a set of potential causative genetic variants inherited in the autosomal dominant pattern. The minor allele frequency (MAF) threshold for known variants was set at 0.2%, all variants exceeding this value were excluded from further analysis. Genetic variants with coverage >10× were retained and analyzed with Variant Studio 3.0 software. Identified candidate variant and its family segregation were verified by Sanger sequencing. By targeted approach, coding and regulatory regions and copy number variants (CNV) of 398 genes reported to be associated with age at menarche by genome-wide association studies were analyzed for rare variants (MAF<0.2%).

Results: The average coverage of each genome was 38× and around 3.8M SNVs and InDels, 5k SVs and 600 CNVs were detected on average per single sample. In a single pedigree a heterozygous premature termination codon in KISS1R NP_115940.2:p.(Cys389Ter), segregating with CPP, was identified. The variant, with CADD score 28.7, was previously reported in a female with hypogonadotropic hypogonadism and has a frequency of 0.04% in GnomAD. The female proband had first signs of puberty at the age of 7.5 years and menarche at 9 years, marginaly advanced bone age, growth spurt at 7–8 years and increased basal and peak luteinizing hormone (LH). Her mother had menarche at 9 years.

Conclusions: To our knowledge this is the second CPP pedigree carrying a KISS1R gene variant. Although trunkating, this variant is considered to be of unknown significance. Functional study would be necessary to determine the implication of identified variant on KISS1R function and reproductive phenotype.