Table 2.
Clinical and MRI brain data of patients with pathogenic and likely pathogenic variants involving leukodystrophy-associated genes.
| Patient ID | Gender | Age at onset | Race | Symptom other than dementia | MRI pattern | Gene | Inheri-tance | Amino acid change | Polyphen-2 score | Polyphen-2 prediction | SIFT4G score | SIFT4G prediction | gnomAD freq (East Asians) | gnomAD freq (South Asians) | gnomAD freq (Non-Finnish Europeans) | ACMG criteria |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1. | F | 34 | Chinese | Parkinson | Frontal | CSF1R | AD | p.T567M | 0.999 | Damaging | 0 | Deleterious | 0 | 0.00003 | 0.00003 | Likely pathogenic |
| 2. | F | 43 | Chinese | ICH | Multifocal SVD | NOTCH3 | AD | p.R544C | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic |
| 3. | F | 44 | Chinese | Stroke | Multifocal SVD | NOTCH3 | AD | p.C134Y | 1.0 | Damaging | 0 | Deleterious | – | – | – | Likely pathogenic |
| 4. | F | 55 | Chinese | Parkinson dystonia | Multifocal SVD | NOTCH3 | AD | p.C1250R | 1.0 | Damaging | 0 | Deleterious | – | – | – | Likely pathogenic |
| 5. | F | 52 | Chinese | Stroke ICH | Multifocal SVD | NOTCH3 | AD | p.R544C | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic |
| 6. | M | 62 | Chinese | ICH epilepsy | Multifocal SVD | NOTCH3 | AD | p.R544C | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic |
| 7. | M | 42 | Chinese | Stroke cerebellar | Multifocal SVD | NOTCH3 | AD | p.R152C | 0.846 | Possibly damaging | 0.035 | Deleterious | – | – | – | Pathogenic |
| 8. | M | 56 | Chinese | Multifocal SVD | NOTCH3 | AD | p.R544C | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic | |
| 9. | M | 63 | Chinese | Stroke parkinson | Multifocal SVD | NOTCH3 | AD | p.R587C | 0.892 | Damaging | 0.102 | Tolerated | 0.0002 | 0 | 0 | Likely pathogenic |
| 10. | M | 48 | Chinese | Stroke parkinson | Multifocal SVD | NOTCH3 | AD | p.R544C | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic |
| 11. | M | 64 | Chinese | Stroke | Multifocal SVD | NOTCH3 | AD | p.R544C | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic |
| 12. | F | 50 | Chinese | Stroke | Multifocal non SVD | NOTCH3 | AD | p.R544C | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic |
| 13. | M | 61 | Chinese | Multifocal non SVD | NOTCH3 | AD | p.R544C | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic | |
| 14. | F | 63 | Filipino | Multifocal SVD | NOTCH3 | AD | p.R544C | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic | |
| 15. | F | 53 | Chinese | ICH psychiatric | Multifocal SVD | NOTCH3 | AD | p.R544C | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic |
| 16. | M | 64 | Chinese | Parkinson psychiatric | Multifocal SVD | NOTCH3 | AD | p.R544C | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic |
| 17. | F | 43 | Chinese | Stroke | Multifocal SVD | NOTCH3 | AD | p.[R544C]; [R544C] | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041 | 0.0001 | 0 | Pathogenic |
| 18. | F | 52 | Chinese | Stroke | Multifocal SVD | NOTCH3 | AD | p.[R544C]; [R607C] | 0.462 | Possibly damaging | 0.042 | Deleterious | 0.0041; 0.00005 | 0.0001; 0 | 0; 0 | Pathogenic; pathogenic |
| 19. | M | 41 | Chinese | Stroke | Multifocal SVD | HTRA1 | AD | p.P285L | 0.995 | Damaging | 0.018 | Deleterious | 0.00005 | 0 | 0 | Pathogenic |
| 20. | M | 59 | Japanese | Stroke | Multifocal SVD | HTRA1 | AD | p.R302* | NA | NA | NA | NA | 0 | 0 | 0.000009 | Pathogenic |
ACMG, American College of Medical Genetics; AD, autosomal dominant; ICH, intracranial hemorrhage; parkinson, parkinsonism; stroke, ischaemic stroke; SVD, small vessel disease.