Pubertal delay in patients with paternally derived 15q11.2-q13 duplication syndrome and MKRN3 overexpression

Duplications of the 15q11.2-q13 region are primarily associated with neurodevelopmental disorders, while their endocrine implications remain poorly defined. The imprinted gene MKRN3, located within this locus, inhibits pubertal onset, and loss-of-function variants cause central precocious puberty. However, the clinical impact of increased MKRN3 dosage remains unclear. This study investigates whether paternally derived 15q11.2-q13 duplications lead to MKRN3 overexpression and are associated with delayed pubertal maturation.

Four patients with confirmed paternal 15q11.2-q13 duplications were retrospectively evaluated. Clinical, auxological, hormonal, and radiological data were collected. Genetic characterization was performed using MS-MLPA, array-CGH, and whole-exome sequencing when possible. MKRN3 expression was assessed by RT-qPCR in peripheral blood samples and compared with Tanner and sex-matched controls.

All patients showed duplications involving the 15q11.2-q13 region with confirmed paternal origin. RT-qPCR showed increased MKRN3 expression in three of the four patients, supporting a potential gene dosage effect. Clinically, patients presented with pubertal abnormalities ranging from delayed puberty with slow progression to hypogonadotropic hypogonadism. Longitudinal data in one patient showed that MKRN3 expression levels during pubertal progression remained elevated compared to controls at both timepoints. In one case, a variant in PROKR2 may have contributed to phenotype.

Paternally derived 15q11.2-q13 duplications are associated with MKRN3 overexpression and delayed pubertal maturation. These findings suggest for the first time in humans a link between increased MKRN3 dosage and pubertal delay, expanding the phenotypic spectrum of dup15q syndrome and highlighting the importance of endocrine monitoring in affected individuals.