Table 1.
Summary of P/LP variants identified by whole genome sequencing.
| Case ID | Gene | Variant/Inheritance | Pop Freq | CADD | ACMG class. | Clinical significance |
|---|---|---|---|---|---|---|
| Individuals with Pathogenic/Likely pathogenic variants considered causative for CP | ||||||
| P169 | GRIN2B | NM_000834.3: c.1739T > A: p.F580Y. Het, inheritance unknown | 0 | 29.8 | Likely pathogenic | Likely pathogenic |
| P176 | ARHGAP31 | NM_020754.2: c.1699del: p.P567Rfs*28. Het, maternal | 0 | . | Likely pathogenic | Likely pathogenic |
| P178a | MFN2 | NM_001127660.1: c.2220 G > A: p.W740*. Het, paternal | 0 | 54 | Likely pathogenic | Likely pathogenic |
| P185 | CLCN2 | NM_001171088.3: c.1598 G > A: p.R533Q. Het, inheritance unknown | 2.00E−04 | 24 | Likely pathogenic | Likely pathogenic |
| CACNA1C | NM_000719.7: c.3568 G > T: p.V1190L. Het, inheritance unknown | 1.22E−05 | 27.6 | Likely pathogenic | ||
| P205 | CFTR | NM_000492.4: c.1520-22del: p.P508del. Hom | 7.17E−03 | 21.3 | Pathogenic | Pathogenic, diagnosed CF. |
| CLCN1 | NM_000083.3: c.2680 C > T: p.R894*. Het, not maternal | 3.18E−03 | 35 | Pathogenic | ||
| P217 | SPAST | Chr2:32347645_32354557del. Compound het, paternal (Supplementary Fig. 6) | 0 | . | Pathogenic | Pathogenic |
| NM_014946.4: c.131 C > T: p.S44L. Compound het, maternal | 4.54E−03 | 21.2 | SPG4 modifier | Modifier | ||
| P225a | SPAST | NM_014946.3:c.1625A > G: p.D542G. Het, maternal, sibs share | 4.13E−04 | 21.2 | Likely pathogenic | Likely pathogenic |
| P233 | SYNE2 | NM_015180.4:c.16153 C > T: p.Q5385*. Het, inheritance unknown | 0 | 44 | Pathogenic | Pathogenic |
| P236 | TUBB4A | NM_006087.4: c.1228 G > A: p.E410K. De novo | 0 | 27.5 | Pathogenic | Pathogenic |
| P708 | KLHL3 | NM_001257195.1: c.1446 G > A: p.W482*. Het, not maternal | 0 | 38 | Pathogenic | Likely pathogenic |
| P712a | NF1 | Chr17:28992701_30408700del. Het, inheritance unknown | 0 | . | Pathogenic | Pathogenic |
| P715 | TTN | NM_001267550.2:c.50473 C > T:pQ16825*. Het, maternal | 0 | 61 | Pathogenic | Likely pathogenic |
| P750b | VCX3A, STS, PNPLA4 | ChrX:6451301_8138000del. Hemi, inheritance unknown (Supplementary Fig. 5) | 0 | . | Pathogenic | Pathogenic |
| P754 | KIDINS220 | NM_020738.2: c.4497del: p.R1499Sfsc9. Het, not maternal. | 0 | . | Likely pathogenic | Likely pathogenic |
| P756 | CACNA1A | NM_001127222.2:c.7249 G > T: p.E2417*. Het, not maternal | 0 | 40 | Likely pathogenic | Likely pathogenic |
| P759 | SETX | NM_015046.7: c.5821_5830del: p. A1941Lfs*6. Het, not maternal. | 0 | . | Pathogenic | Likely pathogenic |
| P763 | CPA6 | NM_020361.5: c.799 G > A: p.G267R. Het, inheritance unknown | 2.06E−03 | 29.1 | Likely pathogenic | Likely pathogenic |
| NM_020361.5: c.619 C > G: p.Q207E. Het, inheritance unknown | 1.43E−03 | 26.2 | Likely pathogenic | |||
| STRADA | NM_001003787.4: c.95-2 A > C splicing. Het, inheritance unknown | 8.23E−06 | 25.8 | Likely pathogenic | Uncertain significance | |
| P784 | GNB1 | NM_002074.5: c.239 T > C: p.I80T. Het, inheritance unknown | 3.98E−06 | 25.6 | Likely pathogenic | Pathogenic |
| P792 | COL4A1 | NM_001845.4: c.1258 G > A: p.G420R. Het, inheritance unknown | 0 | 18.3 | Likely pathogenic | Likely pathogenic |
| P910 | TUBA1A | NM_006009.3: c.50 G > A: p.G17D. Het, inheritance unknown | 0 | 29.2 | Likely pathogenic | Pathogenic |
| P911 | COL4A2 | NM_001846.2: c.3625 G > A: p.G1209R. Het, paternal | 0 | 24.7 | Likely pathogenic | Likely pathogenic |
| P931 | ALDH3A2 | NM_000382.3: c.941_943delinsGGGCTAAAAGTACTGTTGGGG:p.A314_P315delinsGAKSTVGA. Hom, IBD | 0 | . | Pathogenic | Pathogenic |
| P939 | PDGFRB | NM_002609.3: c.2083 C > T: p.R695C. Het, maternal | 1.13E−04 | 32 | Likely pathogenic | Both likely pathogenic |
| PROC | NM_000312.3: c.226 G > A: p.V76M. Het, not maternal | 4.96E−05 | 21.2 | Likely Pathogenic | ||
| P965 | COL4A1 | NM_001845.4: c.4114 G > C: p.G1372R. Het, inheritance unknown | 0 | 23.9 | Pathogenic | Pathogenic |
| P972 | MT‐TL1 | NC_012920.1: m.3243 A > G. Heteroplasmy 58%, Low level detectable in maternal sample | . | . | Pathogenic | Pathogenic |
| P980 | 22q11.2 dup | Chr22:18873001_21469900dup. Validated by array (Supplementary Fig. 3) | 0 | . | Likely pathogenic | Pathogenic |
| P1110 | COL4A2 | NM_001846.2: c.957 + 2 T > C Splicing. Het, not maternal | 0 | 25 | Likely pathogenic | Likely pathogenic |
| P1138 | COL4A2 | NM_001846.2: c.4049 G > A: p.G1350D. Het, maternal | 0 | 25.6 | Likely pathogenic | Likely pathogenic |
Detailed interpretations of variants are shown in Supplementary Table 3. Forty-nine individuals had variants classified as pathogenic or likely pathogenic by ACMG criteria. For twenty-eight of these individuals, the clinically reportable variant was considered likely to be causative for cerebral palsy, while a further nine individuals carried variants considered to be risk factors for cerebral palsy (Table 2). 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), CF cystic fibrosis, del deletion, dup duplication, hemi hemizygous, het heterozygous, hom homozygous, IBD identity by descent, SPG4 Spastic paraplegia 4, *translation termination codon.
aAdditional high impact candidate variants identified in this individual (see Supplementary Table 4).
bAdditional compound heterozygous variants identified in this individual (see Supplementary Table 6).