Table 2.
Causative and likely causative genetic variants identified in the study cohort.
| Case | Gene | Variants | Missense variant | NNSplice | ACMG-AMP criteria | Disease | ||
|---|---|---|---|---|---|---|---|---|
| SIFT | PROVEAN | CADD | ||||||
| D1 | ATXN3 | CAG repeats 15/83 | — | — | — | — | — | SCA3 |
| D2 | ATXN3 | CAG repeats 15/67 | — | — | — | — | — | SCA3 |
| D3 | ATXN3 | CAG repeats 20/72 | — | — | — | — | — | SCA3 |
| D4 | STUB1 | c.101A>G (p.Asn34Ser)* | 0.005 | −4.06 | 26.9 | — | Likely pathogenic (PM1, PM2, PP1, PP2, PP3) | SCA48 |
| R1 | GBA2 | c.2618G>A (p.Arg873His) | 0 | −4.73 | 29.0 | — | Likely pathogenic (PM2, PM3, PP3, PP5) | SPG46 |
| c.2635C>T (p.Arg879Trp)* | 0 | −7.55 | 29.1 | — | Likely pathogenic (PM2, PM3, PM5, PP3) | |||
| R2 | SACS | c.8621_8624 del (p.Ser2874TrpfsTer), homozygous | — | — | — | — | Pathogenic (PVS1, PM2, PP5) | ARSACS |
| R3 | PLA2G6 | c.991G>T (p.Asp331Tyr) | 0.003 | −4.43 | 26.0 | — | Pathogenic (PS3, PM2, PM3, PP2, PP3) | PLAN |
| c.1427+1G>A | — | — | 24.3 | < 0.1 | Pathogenic (PVS1, PM2, PM3, PP5) | |||
| R4 | CAPN1 | c.894G>A (p.Trp298Ter)*, homozygous | — | — | 39.0 | — | Likely pathogenic (PVS1, PM2) | SPG76 |
| S2 | TBCD | c.1340C>T (p.Ala447Val) | 0.002 | −3.68 | 24.5 | — | Likely pathogenic (PM2, PM3, PP3, PP5) | PEBAT |
| c.3365C>T (p.Pro1122Leu) | 0.118 | −6.77 | 24.5 | — | Pathogenic (PS3, PM2, PM3, PP3, PP5) | |||
| S3 | CYP7B1 | c.334C>T (p.Arg112Ter), homozygous | — | — | 23.9 | — | Pathogenic (PVS1, PM2, PP5) | SPG5 |
| S4 | CYP7B1 | c.334C>T (p.Arg112Ter) | — | — | 23.9 | — | Pathogenic (PVS1, PM2, PP5) | SPG5 |
| c.1316T>G (p.Leu439Arg) | 0.145 | −3.49 | 15.08 | — | VUS (PM2, PP5) | |||
| S6 | KIF1A | c.1031C>T (p.Thr344Met)*# | 0 | −5.69 | 25.7 | — | Likely pathogenic (PM1, PM2, PM6, PP3, PP5) | SPG30 |
| S10 | KIF1A | c.761G>A (p.Arg254Gln)# | 0.001 | −3.47 | 27.1 | — | Likely pathogenic (PM1, PM2, PM5, PM6, PP3, PP5) | SPG30 |
| S11 | CAPN1 | c.188dup (p.Val64GlyfsTer) | — | — | — | — | Pathogenic (PVS1, PM2, PM3, PP5) | SPG76 |
| c.1493C>T (p.Pro498Leu) | 0.011 | −9.07 | 23.8 | — | Likely pathogenic (PM1, PM2, PM3, PP2, PP3) | |||
| S12 | CYP7B1 | c.334C>T (p.Arg112Ter), homozygous | — | — | 23.9 | — | Pathogenic (PVS1, PM2, PP5) | SPG5 |
| S13 | SPG11 | c.1602+1G>C* | — | — | 27.7 | < 0.1 | Likely pathogenic (PVS1, PM2) | SPG11 |
| c.3175_3176 delinsTG (p.Ala1059Ter)* | — | — | — | — | Likely pathogenic (PVS1, PM2) | |||
—, not applicable.
*Novel mutation.
#De novo mutation.
ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; D, autosomal dominant inheritance; NNSplice, Splice Site Prediction by Neural Network; PEBAT, progressive encephalopathy with brain atrophy and thin corpus callosum; PLAN, PLA2G6-associated neurodegeneration; R, autosomal recessive inheritance; S, sporadic; VUS, variant of uncertain significance.