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Updated: Jan 4, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Low Frequency of MKRN3 and DLK1 Variants in Chinese Children with Central Precocious Puberty
Ting Chen1, Linqi Chen1, Haiying Wu1
1Department of Endocrinology, Genetics and Metabolism, Children's Hospital of Soochow University, Suzhou, Jiangsu, China.
Insights
This study identified four novel MKRN3 variants in Chinese patients with idiopathic central precocious puberty (ICPP). No DLK1 gene variants were found, suggesting MKRN3 variants are uncommon in this population.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Central precocious puberty (CPP) involves early sexual development before age 8 (girls) or 9 (boys).
- MKRN3 and DLK1 gene variants are recently identified causes of idiopathic CPP (ICPP).
Purpose of the Study:
- To investigate MKRN3 and DLK1 gene variants in Chinese patients with ICPP.
- To analyze the functional impact of identified MKRN3 variants on protein structure and function.
Main Methods:
- Screening of 173 ICPP patients and 43 early puberty patients for MKRN3 variants.
- Screening of 19 ICPP patients for DLK1 variants.
- Bioinformatic analysis of MKRN3 variant impact on protein structure.
Main Results:
- Four novel missense MKRN3 variants (p.Glu380Lys, p.Leu474Met, p.Leu225Val, p.Ile357Met) were identified in five ICPP cases.
- Two MKRN3 variants (p.Glu380Lys, p.Ile357Met) were classified as likely pathogenic.
- No DLK1 variants were detected in any of the screened patients.
Conclusions:
- Novel MKRN3 variants were identified in Chinese ICPP patients.
- MKRN3 variants appear to be relatively uncommon in this Chinese ICPP cohort.
- The study did not find any pathogenic variants in the DLK1 gene among the patients.
Background:
Central precocious puberty (CPP) is defined by gonadotropin-dependent development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. MKRN3 and DLK1 are two genes, disease-causing variants of which have recently been discovered to cause idiopathic CPP.
Methods:
We screened 173 Chinese patients (9 males and 164 females; 9 familial and 164 sporadic) with ICPP and 43 patients (9 males and 34 females; 3 familial and 40 sporadic) with early puberty for variants in MKRN3. We also screened 19 patients with ICPP and early puberty for variants of DLK1 (17 males and 2 females; 5 familial and 14 sporadic).
Results:
We identified four novel missense variants of MKRN3, c.1138G > A (p.Glu380Lys), c.1420T > A (p.Leu474Met), c.673C > G (p.Leu225Val), and c.1071C > G (p.Ile357Met) in two sporadic cases and three familial cases. According to ACMG standards, two MKRN3 variant (p.Glu380Lys and p.Ile357Met) are likely pathogenic, and two others are of uncertain significance. We also performed bioinformatic analysis to evaluate the impact of variants on MKRN3 protein structures, which showed that Ile357Met locates at the zinc-binding region (C3HC4 RING finger motif), while Glu380Lys is spatially extremely close to the C3HC4 RING finger, MKRN-specific Cys-His domain, and the third C3H1 zinc-finger motif region. Per Glu380Lys, Glu with negative charges has been changed into Lys with positive charges, which may affect the hydrogen bond formation between amino acids and the stability of the local structure, thus affecting the binding of zinc iron to MKRN3 protein. Besides, we did not identify any variants of DLK1 gene in our patients.
Conclusions:
In this study, we report four novel MKRN3 variants in patients with ICPP. Moreover, we did not find any variants of DLK1 gene. Variants of MKRN3 are relatively uncommon in Chinese ICPP patients.
