Heterozygous deletions in MKRN3 cause central precocious puberty without Prader-Willi Syndrome.

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 two subjects (13%): a complete deletion of MKRN3 in Patient A (pubertal onset at 7 yrs) and a larger deletion involving MAGEL2, MKRN3, and NDN in Patient B (pubertal onset 5.5 yrs). Both were paternally inherited. Patient B had no typical features of PWS, other than obesity, 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.