Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty

Katie Duckett, Alice Williamson, John Kincaid, Kara Rainbow, Brian Lam, Laura J Corbin, Hilary C. Martin, Ruth Y. Eberhardt, Qin Qin Huang, Matthew Hurles, Raja Brauner, Angela Delaney, Ken McElreavey, Janet Hall, Joel N Hirschhorn, Mark Palmert, Stephanie Seminara, Indi Banerjee, John R B Perry, Nicholas John TimpsonPeter Clayton, Yee-Ming Chan, Ken K Ong*, Stephen O'Rahilly*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

2 Citations (Scopus)


The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than non-carriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.

To determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).

Design, Setting and Participants
We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterised the signalling properties of all non-synonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice breaking in the UK Biobank cohort.

MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 (2.2%), OR = 4.17, p = 0.001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 (0.6%), OR = 1.15, p = 0.779). In 246,328 women from UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (≥16 years) vs normal age at menarche (OR = 1.66, p = 3.90E-07).

We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.
Original languageEnglish
Article numberdgad373
Pages (from-to)e1580-e1587
JournalJournal of Clinical Endocrinology and Metabolism
Issue number12
Early online date20 Jun 2023
Publication statusE-pub ahead of print - 20 Jun 2023

Bibliographical note

Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.

Structured keywords



Dive into the research topics of 'Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty'. Together they form a unique fingerprint.

Cite this