Hae Sang Lee1, Hwal Rim Jeong2, Jung Gi Rho1, Chang Dae Kum1, Kyung Hee Kim1, Do Wan Kim3, Jae Youn Cheong3,4, Seon-Yong Jeong5,6, Jin Soon Hwang1. 1. Department of Pediatrics, Ajou University School of Medicine, Suwon, Republic of Korea. 2. Department of Pediatrics, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea. 3. Ajou Translational Omics Center, Ajou University Medical Center, Suwon, Republic of Korea. 4. Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea. 5. Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea. 6. Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea.
Abstract
Objective: Genetic factors play a critical role in pubertal progression; however, mutations associated with central precocious puberty (CPP) have been reported only in four genes: KISS1, KISS1R, DLK1, and MKRN3. This study aimed to identify novel, potentially pathogenic variants in patients with familial CPP via whole-exome sequencing (WES). Methods: WES analysis was applied in 28 patients (25 girls and three boys) belonging to 14 families, wherein all siblings were diagnosed with CPP. Data analysis aimed to select only very rare variants (minor allele frequency <1%). Nonsense, splice-site, and frameshift variants were considered the most ideal candidate variants. Additionally, non-synonymous missense variants predicted as being deleterious using in silico analysis tools were further considered. Results: The analysis of exome sequencing data resulted in the identification of rare mutations in two promising candidate genes (NOTCH2 and HERC2) in a family. Siblings with CPP exhibited two heterozygous missense mutations (p. Leu15Phe in NOTCH2 and p. Arg4081His in HERC2). Moreover, their parents without history of CPP had a missense variant in either NOTCH2 or HERC2.Conclusions: We identified new candidate genes with potential roles in pubertal development. Digenic inheritance of the two genetic mutations associated with the Notch signaling pathway may have a synergistic effect resulting in CPP.
Objective: Genetic factors play a critical role in pubertal progression; however, mutations associated with central precocious puberty (CPP) have been reported only in four genes: KISS1, KISS1R, DLK1, and MKRN3. This study aimed to identify novel, potentially pathogenic variants in patients with familial CPP via whole-exome sequencing (WES). Methods: WES analysis was applied in 28 patients (25 girls and three boys) belonging to 14 families, wherein all siblings were diagnosed with CPP. Data analysis aimed to select only very rare variants (minor allele frequency <1%). Nonsense, splice-site, and frameshift variants were considered the most ideal candidate variants. Additionally, non-synonymous missense variants predicted as being deleterious using in silico analysis tools were further considered. Results: The analysis of exome sequencing data resulted in the identification of rare mutations in two promising candidate genes (NOTCH2 and HERC2) in a family. Siblings with CPP exhibited two heterozygous missense mutations (p. Leu15Phe in NOTCH2 and p. Arg4081His in HERC2). Moreover, their parents without history of CPP had a missense variant in either NOTCH2 or HERC2.Conclusions: We identified new candidate genes with potential roles in pubertal development. Digenic inheritance of the two genetic mutations associated with the Notch signaling pathway may have a synergistic effect resulting in CPP.