Table 2.
Summary of risk variants, variants of uncertain significance and incidental findings identified by whole genome sequencing.
| Case ID | Gene | Variant/Inheritance | Pop Freq | CADD | ACMG class. | Clinical significance |
|---|---|---|---|---|---|---|
| Individuals with P/LP variants considered risk factors for CP | ||||||
| P165 | TRIM32, ASTN2 | Chr9:119311659_119462832del. Het, inheritance unknown (Supplementary Fig. 2) | 0 | . | Likely pathogenic | Risk factor |
| HTT | NM_002111.8: c.7731 G > A: p.W2577*. Het, inheritance unknown | 0 | 52 | Pathogenic | Uncertain significance | |
| P199a | F8 | NM_000132.3: c.5146 C > A: p.H1716N. Inheritance unconfirmed, father haemophilia A | 0 | 25.5 | Likely pathogenic | Risk factor |
| P214 | 15q11-q13 dup | Chr15:22722801_26749200dup. Likely maternal origin by methylation (Supplementary Fig. 4), inheritance unknown | 0 | . | Pathogenic | Risk factor |
| P710 | F2 | NM_000506.5: c.*97 G > A (G20210A, rs1799963). Het, inheritance unknown | 8.44E−03 | . | Likely pathogenic | Risk factor |
| P747 | F2 | NM_001311257: c.*97 G > A (G20210A, rs1799963). Het, inheritance unknown | 8.44E−03 | . | Likely pathogenic | Risk factor |
| P752 | NKX2-6 | NM_001136271.3: c.455dup: p.Q153Afs*207. Het, maternal | 3.15E−05 | 30 | Pathogenic | Risk factor |
| P779 | F2 | NM_000506.3: c.598 G > A: p.E200K. Het, inheritance unknown | 1.20E−03 | 0 | Risk factor | Risk factor |
| P795 | F2 | NM_001311257: c.*97 G > A (G20210A, rs1799963). Het, inheritance unknown | 8.44E−03 | . | Likely pathogenic | Risk factor |
| P1147 | Chr1q21.1 deletion | Chr1:145382601_145616000del. Het, inheritance unknown (Supplementary Fig. 7) | 0 | . | Pathogenic | Risk factor |
| Individuals with P/LP variants of uncertain clinical significance for CP | ||||||
| P182 | GALC | NM_000153.4: c.1592 G > A: p.R531H. Het, paternal | 3.24E−05 | 29.4 | Pathogenic | Uncertain significance |
| NM_000153.4: c.334 A > G: p.T112A. Het, not paternal | 2.50E−03 | 23 | Likely pathogenic | |||
| P188 | COL4A4 | NM_000092.5: c.4720 C > T: p.Q1574*. Het, inheritance unknown | 0 | 46 | Pathogenic | Uncertain significance |
| P228a | ASTN2 | NM_014010.4: c.2317 C > T: p.Q773*. Het, paternal | 0 | 46 | Pathogenic | Uncertain significance |
| P232 | EGFR | NM_005228.3: c.925 C > T: p.R309*. De novo, not shared by 3 siblings | 0 | 38 | Pathogenic | Uncertain significance |
| P703 | SPG7 | NM_003119.2: c.1045 G > A: p.G349S. Het, inheritance unknown | 8.23E−04 | 26.7 | Likely pathogenic | Uncertain significance |
| P760 | PNPLA6 | NM_001166114.2: c.3058_3061dup: p.R1021Qfs*38. Het, inheritance unknown | 1.25E−04 | 35 | Pathogenic | Uncertain significance, likely in cis by long-read sequencing |
| NM_001166114.2: c.1144del: p.A383Pfs*11. Het, inheritance unknown | 0 | . | Pathogenic | |||
| P778 | VWF | NM_000552.4: c.2561 G > A: p.R854Q. Het, inheritance unknown | 3.47E−03 | 33 | Pathogenic | Uncertain significance |
| P1106 | PIEZO2 | NM_022068.2: c.1444del: p. R482Efs*16. Het, not maternal, not shared by sibling | 0 | . | Likely pathogenic | Uncertain significance |
| P1132 | BUB1B | NM_001211.5: c.1526 C > A: p.S509*. Het, maternal | 0 | 36 | Pathogenic | Uncertain significance |
| Individuals with P/LP variants considered incidental findings for CP | ||||||
| P741 | MITF | NM_006722.2: c.1018 C > T: p.R340C. Het, inheritance unknown | 0 | 33 | Likely pathogenic | Incidental finding |
| P746 | ABCA4 | NM_000350.2: c.6316 C > T: p.R2106C. Het, inheritance unknown | 1.31E−04 | 33 | Pathogenic | Incidental finding |
| NM_000350.2: c.5282 C > G: p.P1761R. Het, inheritance unknown | 0 | 26.5 | Likely pathogenic | Incidental finding | ||
| P749a | GJB2 | NM_004004.5: c.95 G > A: p.R32H. Het, paternal | 3.99E−06 | 25.3 | Pathogenic | Incidental finding |
| P802 | EFEMP1 | NM_001039348.3: c.1033 C > T: p.R345W. Het, not maternal | 0 | 25.9 | Pathogenic | Incidental finding |
Detailed interpretations of variants are shown in Supplementary Table 3. Nine individuals carried variants considered to be risk factors for cerebral palsy, with a further ten individuals carrying at least one variant classified as likely pathogenic/pathogenic by ACMG criteria, but with uncertain clinical significance in the individual. A further four individuals carried ACMG pathogenic/likely pathogenic variants which were considered incidental findings likely contributing to other components of the clinical phenotype, but without a link to CP. Pop. Freq, population frequency of variant in genome aggregation database (gnomAD) or Medical Genome Reference Bank (MGRB).
CADD combined annotation dependent depletion scaled score (phred-like), del deletion, dup duplication, het heterozygous, *translation termination codon.
aAdditional high impact candidate variants identified in this individual (see Supplementary Table 4).