Table 1.
Genes with a significant burden for ultra-rare severe variants.
| Gene | Samples | smMIP (AC ≤ 3) Combined (This study | Published) | ExAC non-psych (AC ≤ 9) | Mutation burden test | |||||
|---|---|---|---|---|---|---|---|---|---|
| LGD | MIS30 | LGD | MIS30 | LGD p-value | MIS30 p-value | FDR Significance | FWER Significance | ||
| SCN2A | 19,847 | 33 (12|23) | 25 (4|23) | 1 | 11 | 2.09E−16 | 1.63E−06 | LGD MIS30 | LGD |
| GRIN2B | 19,847 | 14 (8|9) | 14 (5|10) | 0 | 6 | 5.82E−08 | 3.08E−04 | LGD MIS30 | LGD |
| ADNP | 19,847 | 28 (13|18) | 3 (1|2) | 1 | 3 | 6.89E−14 | 2.64E−01 | LGD | LGD |
| CHD8 | 19,847 | 25 (8|17) | 21 (10|11) | 5 | 32 | 3.03E−09 | 9.77E−02 | LGD | LGD |
| POGZ | 19,847 | 16 (7|9) | 13 (3|11) | 2 | 10 | 4.20E−07 | 8.24E−03 | LGD | LGD |
| DYRK1A | 19,847 | 16 (4|12) | 8 (3|5) | 2 | 9 | 4.20E−07 | 1.12E−01 | LGD | LGD |
| SETD5 | 19,847 | 15 (3|12) | 19 (8|15) | 3 | 12 | 5.28E−06 | 3.68E−04 | LGD MIS30 | |
| DDX3X | 19,847 | 10 (4|7) | 7 (4|3) | 1 | 0 | 5.41E−05 | 2.41E−04 | LGD MIS30 | |
| ANK2 | 19,538 | 17 (4|14) | 61 (29|46) | 11 | 86 | 7.61E−04 | 2.16E−03 | LGD MIS30 | |
| KMT5B | 19,538 | 7 (1|6) | 8 (3|7) | 1 | 2 | 1.32E−03 | 1.63E−03 | LGD MIS30 | |
| CTNNB1 | 19,847 | 10 (1|9) | 5 (0|5) | 0 | 11 | 6.80E−06 | 5.65E−01 | LGD | |
| ZBTB18* | 16,321 | 8 (8|-) | 3 (3|-) | 0 | 2 | 2.37E−05 | 1.19E−01 | LGD | |
| KMT2A | 19,077 | 13 (5|9) | 29 (9|22) | 3 | 42 | 2.86E−05 | 2.82E−02 | LGD | |
| ASXL3* | 19,077 | 11 (1|10) | 3 (0|3) | 2 | 7 | 6.32E−05 | 6.06E−01 | LGD | |
| SIN3A | 19,538 | 8 (2|6) | 12 (3|10) | 0 | 20 | 6.73E−05 | 2.32E−01 | LGD | |
| NAA15 | 19,538 | 13 (1|12) | 6 (3|3) | 4 | 10 | 1.07E−04 | 3.43E−01 | LGD | |
| HNRNPU* | 16,321 | 8 (8|-) | 0 (0|-) | 2 | 0 | 6.26E−04 | 1 | LGD | |
| DSCAM | 19,847 | 11 (4|8) | 43 (21|34) | 3 | 64 | 2.83E−04 | 2.01E−02 | LGD | |
| TRIO | 19,847 | 11 (6|5) | 22 (8|15) | 3 | 35 | 2.83E−04 | 1.17E−01 | LGD | |
| WAC* | 19,847 | 9 (2|7) | 12 (1|12) | 2 | 14 | 6.49E−04 | 6.65E−02 | LGD | |
| RELN* | 19,847 | 11 (3|8) | 45 (23|37) | 4 | 78 | 7.68E−04 | 8.43E−02 | LGD | |
| PASK* | 19,077 | 41 (17|29) | 9 (5|6) | 50 | 12 | 1.28E−03 | 1.38E−01 | LGD | |
| ZMYM2* | 19,077 | 11 (7|7) | 4 (2|2) | 5 | 5 | 1.38E−03 | 2.61E−01 | LGD | |
| SMARCC2 | 19,847 | 7 (0|7) | 4 (0|4) | 1 | 7 | 1.42E−03 | 4.43E−01 | LGD | |
| KAT6A* | 16,321 | 8 (8|-) | 7 (7|-) | 3 | 24 | 1.76E−03 | 7.49E−01 | LGD | |
| CHAMP1* | 16,321 | 6 (6|-) | 1 (1|-) | 1 | 1 | 1.84E−03 | 4.59E−01 | LGD | |
| ASH1L | 19,847 | 10 (5|6) | 39 (17|28) | 4 | 65 | 1.88E−03 | 7.38E−02 | LGD | |
| NFIA | 19,847 | 5 (2|4) | 3 (1|2) | 0 | 2 | 2.61E−03 | 1.69E−01 | LGD | |
| MYT1L* | 19,077 | 7 (0|7) | 10 (4|6) | 2 | 17 | 3.94E−03 | 2.57E−01 | LGD | |
| DLG4 | 19,538 | 7 (2|5) | 7 (2|5) | 2 | 11 | 4.38E−03 | 2.81E−01 | LGD | |
| CHD2* | 19,847 | 8 (5|4) | 17 (3|16) | 3 | 18 | 4.73E−03 | 1.84E−02 | LGD | |
| NEXMIF* | 16,321 | 6 (6|-) | 3 (3|-) | 2 | 3 | 5.71E−03 | 1.93E−01 | LGD | |
| BRPF1* | 16,321 | 5 (5|-) | 13 (13|-) | 2 | 27 | 1.65E−02 | 2.40E−01 | LGD | |
| PHF12* | 16,321 | 6 (6|-) | 8 (8|-) | 2 | 17 | 5.71E−03 | 3.32E−01 | LGD | |
| SATB2* | 16,321 | 5 (5|-) | 4 (4|-) | 1 | 7 | 6.02E−03 | 3.26E−01 | LGD | |
| SPEN* | 16,321 | 9 (9|-) | 31 (31|-) | 6 | 57 | 6.25E−03 | 4.26E−02 | LGD | |
| AHNAK* | 19,538 | 26 (11|17) | 11 (5|9) | 30 | 10 | 7.26E−03 | 2.70E−02 | LGD | |
| ZNF292* | 19,077 | 9 (3|6) | 0 (0|0) | 5 | 6 | 7.52E−03 | 1 | LGD | |
| PHIP* | 19,847 | 10 (3|7) | 18 (3|15) | 6 | 24 | 7.96E−03 | 5.96E−02 | LGD | |
| TNRC6B | 19,847 | 10 (2|8) | 12 (2|10) | 6 | 16 | 7.96E−03 | 1.12E−01 | LGD | |
| KMT2E* | 19,538 | 9 (5|5) | 10 (3|7) | 5 | 15 | 8.48E−03 | 1.92E−01 | LGD | |
| TRIP12 | 19,847 | 7 (1|6) | 16 (8|10) | 3 | 25 | 1.15E−02 | 1.52E−01 | LGD | |
| TBR1* | 19,847 | 5 (2|3) | 3 (2|1) | 1 | 6 | 1.17E−02 | 5.49E−01 | LGD | |
| SETBP1* | 19,847 | 6 (2|4) | 9 (7|5) | 2 | 14 | 1.22E−02 | 2.43E−01 | LGD | |
| PHF7* | 19,538 | 9 (4|5) | 3 (3|0) | 6 | 6 | 1.56E−02 | 5.40E−01 | LGD | |
| TCF12* | 16,321 | 9 (9|-) | 12 (12|-) | 8 | 18 | 1.79E−02 | 7.34E−02 | LGD | |
| SLC6A1 | 19,847 | 1 (0|1) | 18 (8|12) | 0 | 9 | 3.04E−01 | 1.11E−04 | MIS30 | |
| BRAF* | 16,321 | 1 (1|-) | 11 (11|-) | 2 | 7 | 6.02E−01 | 2.03E−03 | MIS30 | |
Fisher’s exact test (one-sided) for LGD and MIS30 variants from smMIP sequencing compared to the ExAC (r0.3) non-psych subset identified 48 genes significant at the FDR level, of which, six genes reach FWER significance. The FDR significance threshold qmutBurden < 0.05 was corrected by the Benjamini–Hochberg method for 125 genes in this study; the FWER significance threshold pmutBurden < 1.25E−06 was corrected by the Bonferroni method for 20,000 genes in human genome and two tests performed (LGD and MIS30 variants). *Indicates 25 genes showing new mutational burden significance in case-control analysis of ultra-rare LGD and MIS30 variants in this study. See Supplementary Data 10 for underlying data.