Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty.
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Duckett Katie, Williamson Alice, Kincaid John W R, Rainbow Kara, Corbin Laura J, Martin Hilary C, Eberhardt Ruth Y, Huang Qin Qin, Hurles Matthew E, He Wen, Brauner Raja, Delaney Angela, Dunkel Leo, Grinspon Romina P, Hall Janet E, Hirschhorn Joel N, Howard Sasha R, Latronico Ana C, Jorge Alexander A L, McElreavey Ken, Mericq Verónica, Merino Paulina M, Palmert Mark R, Plummer Lacey, Rey Rodolfo A, Rezende Raíssa C, Seminara Stephanie B, Salnikov Kathryn, Banerjee Indraneel, Lam Brian Y H, Perry John R B, Timpson Nicholas J, Clayton Peter, Chan Yee-Ming, Ong Ken K, O'Rahilly Stephen
Аннотация
OBJECTIVE: This work aimed 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).
METHODS: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous 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.
RESULTS: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07).
CONCLUSION: 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.