Table 1.
Frequencies of validated MC3R loss of function variants in delayed puberty cohorts
| PLoF | CLoF | Combined PLoF and CLoF | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cohort | Total No. | No. carriers | Frequency (per 1000) | OR vs ALSPAC | 95% CI | P | No. carriers | Frequency (per 1000) | OR vs ALSPAC | 95% CI | P | No. carriers | Frequency (per 1000) | OR vs ALSPAC | 95% CI | P |
| Manchester UK CDGP | 84 | 0 | 0 | — | — | — | 1 | 11.9 | 11.44 | 0.25-95.9 | .097 | 1 | 11.9 | 2.25 | 0.06-13.4 | .366 |
| DPGen | 278 | 5 | 18.0 | 4.27 | 1.31-10.9 | .009 | 2 | 7.2 | 6.92 | 0.68-39.0 | .050 | 7 | 25.2 | 4.75 | 1.81-10.6 | .001 |
| Total DP: | 362 | 5 | 13.8 | 3.28 | 1.01-8.34 | .024 | 3 | 8.3 | 7.97 | 1.28-37.5 | .013 | 8 | 22.1 | 4.17 | 1.70-8.91 | .001 |
| nIHH | 657 | 2 | 3.0 | 0.72 | 0.08-2.79 | ≥.999 | 2 | 3.0 | 2.93 | 0.29-16.4 | .194 | 4 | 6.1 | 1.15 | 0.30-3.13 | .779 |
| ALSPAC | 5774 (9966) | 42 | 4.2 | — | — | — | 6 | 1.0 | — | — | — | — | 5.3 | — | 0 | — |
All MC3R coding variants were experimentally characterized as PLoF (Vmax >25% Vmax [WT] and Vmax ≤75% Vmax [WT]) or CLoF (Vmax ≤25% Vmax [WT]). ORs, 95% CIs, and P values for frequency of LoF mutations compared to ALSPAC controls were calculated using the Fisher exact test. For CLoF variants, data were available for 5774 ALSPAC individuals, and for PLoF variants 9966 ALSPAC individuals. For combined PLoF and CLoF, a combined frequency in ALSPAC was calculated.
Abbreviations: ALSPAC, Avon Longitudinal Study of Parents and Children; CDGP, constitutional delay of growth and puberty; CLoF, complete loss-of-function; DP, delayed puberty; LoF, loss-of-function; MC3R, melanocortin 3 receptor; nIHH, normosmic idiopathic hypogonadotropic hypogonadism; OR, odds ratio; PLoF, partial loss-of-function; WT, wild-type.