To estimate the fraction of LGD and Mis3 variants carrying risk (ELGD and EMis3), we calculated M1 and M2, the observed rates of de novo LGD or Mis3 variants per TD proband and per SSC sibling control, respectively. More specifically, for LGD variants, M1 = (39/484) and M2 = (22/602), and therefore, we estimated E as: E = ((M1−M2)/M1) = ((39/484) − (22/602)/(39/484)) = 0.546. For Mis3 variants, M1 = (303/484) and M2 = (158/602), and therefore, we estimated E as: E = ((M1−M2)/M1) = ((303/484) − (158/602)/(303/484) = 0.206.
