Table 5.
Identification of NF1 and Legius syndrome based on testing sporadic childhood cases with > 5 CAL with no other features of NF1 and extrapolation to reassurance of negative testing with both RNA and DNA based testing.
| Clear pathogenic NF1 mutation (definite NF1) |
Missense or other vus probably disease causing (probable NF1) |
SPRED1 mutation (Legius syndrome) | No mutation (probable sporadic CAL or other disorder) | Likelihood of a missed mutation assuming sensitivity of (RNA) and (DNA) | Likelihood that no full germline NF1 mutation exists | Likelihood has NF1 if NF1 testing negative | |
|---|---|---|---|---|---|---|---|
| Actual testing of 71 samples | 62% (n = 44)a | 4.2% (n = 3) | 8.4% (n = 6) | 25.4% (n = 18) | – | ||
| Predicted likelihood based on 95.8% sensitivity from RNA testing | 64.9% | 4.2% | 8.4% | 22.5% | 2.90% (95.79%) | 2.9/25.4 = 11.4% | 11.4% 1 in 9 |
| Predicted identification rate from DNA testing | 55.7%b | 8.6%+ | 8.4% | 27.3% | 4.8% (93.05%) |
4.8/27.3 = 17.6 | 17.6% 1 in 6 |
a
Includes 4 missense mutations shown to have arisen de novo by exclusion in parents.
b
The reduction from RNA testing assumes 2.9% with deep intronic splicing mutations (overall 1.9% of samples) will be missed and that a further 6.6% with splicing variants outside consensus splice site or missense mutations causing splicing will not be classifiable and moved to the VUS column.