Heterozygous Deletions in MKRN3 Cause Central Precocious Puberty Without Prader-Willi Syndrome

J Clin Endocrinol Metab. 2020 Aug 1;105(8):2732-2739. doi: 10.1210/clinem/dgaa331.


Context: Loss-of-function mutations in the imprinted genes MKRN3 and DLK1 cause central precocious puberty (CPP) but whole gene deletions have not been reported. Larger deletions of the chromosome 15q11-13 imprinted locus, including MKRN3, cause Prader-Willi syndrome (PWS). CPP has been reported in PWS but is not common, and the role of MKRN3 in PWS has not been fully elucidated.

Objective: To identify copy number variants in puberty-related, imprinted genes to determine their role in CPP.

Methods: Probands with idiopathic CPP had chromosomal microarray (CMA) and targeted deletion/duplication testing for MKRN3 and DLK1.

Results: Sixteen female probands without MKRN3 or DLK1 variants identified by Sanger sequencing were studied. Whole gene deletions of MKRN3 were identified in 2 subjects (13%): a complete deletion of MKRN3 in Patient A (pubertal onset at 7 years) and a larger deletion involving MAGEL2, MKRN3, and NDN in Patient B (pubertal onset 5.5 years). Both were paternally inherited. Patient B had no typical features of PWS, other than obesity, which was also present in her unaffected family.

Conclusions: We identified 2 cases of whole gene deletions of MKRN3 causing isolated CPP without PWS. This is the first report of complete deletions of MKRN3 in patients with CPP, emphasizing the importance of including copy number variant analysis for MKRN3 mutation testing when a genetic diagnosis is suspected. We speculate that there is a critical region of the PWS locus beyond MKRN3, MAGEL2, and NDN that is responsible for the PWS phenotype.

Trial registration: ClinicalTrials.gov NCT01500447.

Keywords: MKRN3; Prader-Willi syndrome; Precocious puberty; copy number variants; deletions; genetics.

Publication types

  • Observational Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium-Binding Proteins / genetics
  • Child
  • Child, Preschool
  • DNA Copy Number Variations
  • DNA Mutational Analysis
  • Gene Deletion*
  • Genetic Testing
  • Heterozygote*
  • Humans
  • Infant
  • Membrane Proteins / genetics
  • Menarche / genetics
  • Prader-Willi Syndrome / diagnosis*
  • Prader-Willi Syndrome / genetics
  • Puberty, Precocious / genetics*
  • Ubiquitin-Protein Ligases / genetics*


  • Calcium-Binding Proteins
  • DLK1 protein, human
  • Membrane Proteins
  • MKRN3 protein, human
  • Ubiquitin-Protein Ligases

Associated data

  • ClinicalTrials.gov/NCT01500447