Clinical severity correlates with in vitro residual FANCB function. (A) The median time to death was earlier in the WGD/truncation variant group (individuals 1, 2, 3, 4, 6, 11, 13, and 14) than in the missense group (individuals 16, 17, 18, 20, and 21) but was not statistically significant (log-rank test, 0.5198; P = .4709; hazard ratio [HR], 1.693; 95% confidence interval [CI], 0.398-7.198). Individuals excluded from this analysis are detailed in the supplemental methods. (B) The median time to hematologic disease was earlier in the WGD/truncation variant group (individuals 3, 6, 11, and 14) than in the missense group (individuals 16, 17, 18, 20, and 21) but was also not statistically significant (log-rank test, 2.3962; P = .1216; HR, 3.058; 95% CI, 0.669-13.973). Individuals excluded from this analysis are detailed in the supplemental methods. (C) Survival and onset of hematologic manifestations (heme onset defined as the onset of bone marrow failure, myelodysplastic syndrome, or leukemia, whichever came first) tends to correlate with residual function, such as mitomycin C sensitivity or quantity of FANCD2 foci. (D) A majority of the transcripts in the individual carrying c.1435T>G (predicted to express p.W479G) variant showed aberrant splicing and exon 7 skipping, which should result in an out-of-frame truncated protein. Although the expression level of c.1435T>G encoding the missense variant p.W479G was lower, its functional characteristics were near normal, correlating with the relatively milder phenotype in this individual. In contrast, the individual carrying splice site variant (c.1496+1G>A), which resulted in the only product that lacked exon 7, died on postnatal day 1. EV indicates vector-only control.