Table 2.
Genes reaching new de novo enrichment significance.
| Gene | DNM All (denovo-db | SPARK-27K) | CH model | denovolyzeR | Significance (union of two models) | Reported significance | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| dnLGD | dnMIS | dnMIS30 | dnLGD p-value | dnMIS p-value | dnMIS30 p-value | dnALT p-value | dnLGD p-value | dnMIS p-value | dnALT p-value | FDR | FWER | Coe253 | ASC102 | DDD299 | |
| New FDR significance | |||||||||||||||
| UIMC1 | 0 (0|0) | 6 (4|2) | 0 (0|0) | 1 | 1.67E−02 | 1 | 2.94E−02 | 1 | 5.00E−05 | 2.01E−04 | dnMIS dnALT | – | No | No | No |
| SMARCC2 | 4 (2|2) | 2 (2|0) | 0 (0|0) | 6.53E−05 | 4.44E−01 | 1 | 8.20E−03 | 5.17E−05 | 3.76E−01 | 4.49E−03 | dnLGD | – | No | Yes | No |
| NRXN1 | 1 (1|0) | 7 (5|2) | 1 (1|0) | 2.13E−01 | 4.70E−03 | 2.06E−01 | 2.30E−03 | 1.57E−01 | 1.54E−03 | 4.87E−04 | dnALT | – | No | Yes | No |
| HNRNPK | 2 (2|0) | 2 (1|1) | 2 (1|1) | 1.16E−03 | 3.89E−02 | 2.30E−04 | 5.00E−04 | 6.27E−03 | 9.96E−02 | 4.38E−03 | dnALT | – | No | No | Yes |
| GABRG2 | 1 (0|1) | 4 (3|1) | 3 (3|0) | 2.41E−01 | 1.52E−01 | 1.29E−03 | 8.69E−02 | 1.22E−01 | 1.47E−03 | 4.16E−04 | dnALT | – | No | No | No |
| New FWER significance | |||||||||||||||
| ANK2 | 9 (6|3) | 5 (5|0) | 1 (1|0) | 1.13E−05 | 9.97E−01 | 6.88E−01 | 6.08E−01 | 6.09E−09 | 3.03E−01 | 1.22E−04 | dnLGD dnALT | dnLGD | Yes | Yes | No |
| TBR1 | 4 (3|1) | 3 (2|1) | 1 (0|1) | 1.93E−07 | 9.30E−03 | 2.60E−02 | 6.81E−07 | 2.01E−06 | 6.88E−02 | 9.41E−05 | dnLGD dnALT | dnLGD | Yes | Yes | No |
| PHF12 | 4 (3|1) | 1 (1|0) | 0 (0|0) | 1.06E−07 | 3.02E−01 | 1 | 6.08E−05 | 4.00E−06 | 6.83E−01 | 9.15E−03 | dnLGD dnALT | dnLGD | Yes | Yes | No |
| TCF7L2 | 4 (3|1) | 5 (3|2) | 3 (3|0) | 7.36E−06 | 2.30E−03 | 3.70E−04 | 1.26E−06 | 1.56E−05 | 9.05E−04 | 3.47E−07 | dnLGD dnALT | dnALT | Yes | Yes | Yes |
| SETD2 | 6 (5|1) | 2 (2|0) | 1 (1|0) | 4.39E−06 | 8.43E−01 | 2.56E−01 | 3.59E−02 | 3.30E−07 | 6.63E−01 | 4.55E−03 | dnLGD | dnLGD | Yes | No | Yes |
| CASZ1 | 6 (4|2) | 2 (0|2) | 1 (0|1) | 8.43E−07 | 8.17E−01 | 2.17E−01 | 2.35E−02 | 1.16E−09 | 7.09E−01 | 5.10E−03 | dnLGD | dnLGD | Yes | No | No |
| NSD2 | 5 (4|1) | 1 (1|0) | 1 (1|0) | 4.57E−07 | 7.20E−01 | 1.35E−01 | 3.40E−03 | 1.19E−07 | 7.82E−01 | 6.60E−03 | dnLGD | dnLGD | Yes | No | Yes |
Five genes newly reached FDR significance and seven genes reached FWER significance in the de novo enrichment analysis, compared to Coe et al.25, using the same methods (CH model and denovolyzeR) with DNMs in 17,426 NDD trios combined from denovo-db (v1.5) and SPARK-27K. The FDR significance threshold qdnEnrich < 0.05 was corrected by the Benjamini–Hochberg method for genes in each method (18,946 genes in CH model and 19,618 genes in denovolyzeR); the FWER significance threshold pdnEnrich < 3.64E−07 was corrected by the Bonferroni method for 19,618 genes and seven tests (dnLGD, dnMIS, dnMIS30, and dnALT variants in CH model, and dnLGD, dnMIS, and dnALT variants in denovolyzeR). Coe253 indicates whether the gene is in the 253 genes reported significant (FDR 5%) in Coe et al.25; ASC102 indicates whether the gene is in the 102 genes reported as significant (FDR 10%) in Satterstrom et al.8; and DDD299 indicates whether the gene is in the 299 genes reported as significant in Kaplanis et al.31. Note different methods and significant threshold were applied in those three studies. See Supplementary Data 10 for underlying data.