Background
Methods
Results
Genetic spectrum
Family No. | Nucleotide change1 | Amino acid change | Mutation type | Exon | Allele frequency in 1846 controls | dbSNP | EVS | PhyloP2[-14,1;6,4] | Grantham distance3[0–215] | In-silico predictions4 | Novel variant | Pathogenicity class5 |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Patients with 2 pathogenic or likely pathogenic
SACS
variants
| ||||||||||||
#1 index
| c.9305_9306insT | p.Leu3102Phefs*8 | frame shift | 10 | 0 | - | - | NA | NA | NA | yes |
Pathogenic (class 5)
|
c.9305_9306insT | p.Leu3102Phefs*8 | |||||||||||
#1 sister | see above | |||||||||||
#2
| c.2182C>T | p.Arg728* | nonsense | 9 | 0 | - | - | ND | NA | NA | no6 |
Pathogenic (class 5)
|
c.13056delT | p.Phe4352Leufs*11 | frame shift | 10 | 0 | - | - | NA | NA | NA | yes |
Pathogenic (class 5)
| |
#3 index
| c.3769G>T | p.Gly1257* | nonsense | 10 | 0 | - | - | ND | NA | NA | yes |
Pathogenic (class 5)
|
c. 8584A>T | p.Lys2862* | nonsense | 10 | 0 | - | - | ND | NA | NA | yes |
Pathogenic (class 5)
| |
#3 sister | see above | |||||||||||
#4 index
| c.11542_11544del | p.Ile3848del | in-frame deletion | 10 | 0 | - | - | NA | NA | NA | yes |
Likely pathogenic (VUS class 4)
|
c.11542_11544del | p.Ile3848del | |||||||||||
#4 brother | see above | |||||||||||
#5 index
| c.2387delT | p.Leu796Tyrfs*13 | frame shift | 10 | 0 | - | - | NA | NA | NA | yes |
Pathogenic (class 5)
|
c.11984_11986 dupTGT | p.L3995dup | in-frame duplication | 10 | 0 | - | - | NA | NA | NA | yes |
Likely pathogenic (VUS class 4)
| |
#5 sister | see above | |||||||||||
#6 | c.11624 G>A | p.Arg3875His | missense | 10 | 0 | - | - | 6.34 | 29 | Deleterious | yes |
Likely pathogenic (VUS class 4)
|
c.1647_1658del | p.Leu549_Leu552del | In-frame deletion | 8 | 0 | - | - | NA | NA | NA | yes |
Likely pathogenic (VUS class 4)
| |
c.13538 G>A | p.Ser4513Asn | missense | 10 | 0 | rs138328181 (0% ESP Cohort pop) | 0.02% (EA), 0% (AA) | 3.43 | 46 | Contradictory | yes |
Uncertain (VUS class 3)
| |
#7 | c.5544dupA | p.Val1849Serfs*48 | frame shift | 10 | 0 | - | - | NA | NA | NA | yes |
Pathogenic (class 5)
|
c.12603C>A | p.Tyr4201* | nonsense | 10 | 0 | - | - | ND | NA | NA | yes |
Pathogenic (class 5)
| |
#8 | c.7277 G>C | p.Arg2426Pro | missense | 10 | 0 | - | - | 5.69 | 103 | Deleterious | yes |
Likely pathogenic (VUS class 4)
|
c.8920_8923dup | p.Tyr2975Phefs*29 | frame shift | 10 | 0 | - | - | NA | NA | NA | yes |
Pathogenic (class 5)
| |
#9 | c.4954C>T | p.Gln1652* | nonsense | 10 | 0 | - | - | ND | NA | NA | yes |
Pathogenic (class 5)
|
c.5125C>T | p.Gln1709* | nonsense | 10 | 0 | - | - | ND | NA | NA | no6 |
Pathogenic (class 5)
| |
Patients with 2
SACS
variants of uncertain clinical significance class 3 (VUS3)
| ||||||||||||
#10 | c.1373C>T | p.Thr458Ile | missense | 8 | 14/3500 | rs61729954 (0.3% ESP Cohort pop; 3.1% AGI ASP pop) | 0.33% (EA); 0.05% (AA) | 6.26 | 89 | Deleterious | yes |
Uncertain (VUS class 3)
|
c.1373C>T | p.Thr458Ile | |||||||||||
#11 | c.1373C>T (see patient #10) | p.Thr458Ile | missense | 8 | 14/3500 | rs61729954 (0.3% ESP Cohort pop; 3.1% AGI ASP pop) | 0.33% (EA); 0.05% (AA) | 6.26 | 89 | Deleterious | yes |
Uncertain (VUS class 3)
|
c.2983 G>T | p.Val995Phe | missense | 10 | 11/3500 | rs142967124 (0.1% ESP Cohort pop) | 0.24% (EA); 0.02% (AA) | -0.2 | 50 | Contradictory | yes |
Uncertain (VUS class 3)
|
Phenotypic spectrum of index patients with two ARSACS variants of at least probable pathogenicity
Family No. | SACS variant | Ethnical background | Current age (y)/sex | Age at onset (y) | First clinical sign | Current SARA | Cerebellar ataxia | Areflexia muscle tendon reflexes | Pyramidal features | Autonomic signs |
---|---|---|---|---|---|---|---|---|---|---|
patients with 2 likely pathogenic
SACS
variants
| ||||||||||
#1 index
| p.[Leu3102Phefs*8];[Leu3102Phefs*8] | Turkey | 31/f | 1 | delayed motor development | 12 | Dysarthria, nystagmus, dysmetria UE | ATR | spasticity LE>UE; Bab +/+ | urge incontinence urine |
#1 sister | see above | 30/f | 11 | gait disturbance | 10 | Nystagmus, dysmetria UE+LE | ATR | spasticity LE>UE; Bab +/+ | urge incontinence urine | |
#2
| p.[Arg728*];[Phe4352Leufs*11] | German | 38/f | 6 | gait disturbance | 22 | nystagmus, dysmetria UE+LE | ATR | spasticity, Bab +/+ | urge incontinence urine |
#3 index
| p.[Gly1257*]; [Lys2862*] | Greek | 40/m | 18 | gait disturbance | 22 | nystagmus, dysarthria, dysmetria UE+LE | - | spasticity, Bab +/+ | urge incontinence urine |
#3 sister | see above | 36/f | 15 | gait disturbance | n.d. | n.k. | n.k. | n.k. | urge incontinence urine | |
#4 index
| p.[Ile3848del]; [Ile3848del] | Turkey | 13/m | 3 | generalized muscle weakness, pes planus | 2 | - | - | none; Bab -/- | - |
#4 brother | see above | 6/m | pes planus | 1 | - | - | none; Bab -/- | - | ||
#5; index
| p.[Leu796Tyrfs*13];[L3995dup] | German | 27/f | 2 | gait disturbance | 25 | nystagmus, dysmetria UE+LE | ATR | spasticity, Bab +/+ | urge incontinence urine & faeces |
#5, sister | see above | 25/f | 2 | gait disturbance | n.a. | Dysarthria, dysmetria LE > UE | ATR | none, Bab -/- | urge incontinence urine | |
#6 | p.[Arg3875His]; [Leu549_Leu552del]; [Ser4513Asn] | Macedonia | 30/m | 1 | gait disturbance | 9 | dysmetria UE+LE - | ATR | spasticity, Bab+/+ | - |
#7 | p.[Val1849Serfs*48]; [Tyr4201*] | German | 50/f | 28 | gait disturbance | n.a. | nystagmus, dysarthria, dysmetria UE+ UE | ATR | spasticity; Bab +/+ | urge incontinence |
#8 | p.[Arg2426Pro]; [Tyr2975Phefs*29] | German | 6/m | 2 | gait disturbance | 9 | nystagmus, dysarthria, dysmetria UE+LE | - | none; Bab -/- | incontinence |
#9 | p.[Gln1652*]; [Gln1709*] | German | 41/m | 2 | gait disturbance | n.a. | nystagmus, dysarthria, dysmetria UE+LE | ATR | spasticity; Bab -/- | urge incontinence, erectile dysfunction |
patients with 2
SACS
variants of unknown significance
| ||||||||||
#10 | p.[Thr458Ile]; [Thr458Ile] | Turkey | 44/m | 30 | gait disturbance | 8 | nystagmus, slight dysmetria UE + LE, no dysarthria | - | none; Bab -/- | urge incontinence |
#11 | p.[Thr458Ile]; [Val995Phe] | German | 43/m | 20 | gait ataxia | 21 | cerebellar oculomotor disturbance, dysarthria, dysphagia, intention tremor, dysmetria UE+LE | - | spasticity; Bab+/+ | - |
family No. | SACS variants | Sensory nerve conduction sural or radial nerve | Motor nerve conduction tibial or ulnar nerve | Motor evoked potentials | Cerebellar atrophy | Arachnoid cyst posterior fossa | T2 hypo-intensities pons | T2 hyper-intensities lateral pons/MCP | Thickening of MCP | Bilateral parietal atrophy | Thin corpus callosum (MRI) |
---|---|---|---|---|---|---|---|---|---|---|---|
patients with 2 likely pathogenic
SACS
variants
| |||||||||||
#1 | p.[Leu3102Phefs*8];[Leu3102Phefs*8] | Sur: no SNAP Rad: no SNAP | Tib:reduced CMAP+MNCV Uln: reduced MNCV | prolonged UE+LE | +, vermal | + | + | + | + | + | + |
#2 | p.[Arg728*];[Phe4352Leufs*11] | Sur: no SNAP Rad: no SNAP | Tib: reduced MNCV Uln: reduced MNCV | prologned UE, not evoked LE | +, pancerebellar | + | + | + | + | + | + |
#3 | p.[Gly1257*];[Lys2862*] | Sur: no SNAP Rad: no SNAP | Tib: no MSAP Uln: reduced MNCV | prolonged UE, not evoked LE | +, pancerebellar | + | + | + | + | + | + |
#4 | p.[Ile3848del];[Ile3848del] | Sur: no SNAP Rad: reduced CMAP+SNCV | Tib: reduced MNCV Uln: reduced MNCV | prolonged UE, not evoked LE | -, only asymmetry of cerebellar hemispheres | + | + | + | + | - | + |
#5 | p.[Leu796Tyrfs*13];[L3995dup] | Sur: no SNAP Rad: reduced CMAP+SNCV | Tib: reduced CMAP+MNCV Uln: reduced MNCV | prolonged UE, not evoked LE | +, vermal | + | + | + | + | - | + |
#6 | p.[Arg3875His]; [Leu549_Leu552del]; [Ser4513Asn] | Sur: reduced CMAP+SNCV Rad: reduced CMAP+SNCV | Tib: reduced CMAP+MNCV Uln: reduced MNCV | prolonged UE, not evoked LE | +, vermal | + | + | + | + | + | - |
#7 | p.[Val1849Serfs*48]; [Tyr4201*] | Sur: reduced CMAP+SNCV | Tib: reduced CMAP+MNCV | not evoked LE | +, pancerebellar | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. |
#8 | p.[Arg2426Pro]; [Tyr2975Phefs*29] | Sur: normal | Tib: normal | not done | +, vermal | - | + | + | + | - | - |
#9 | p.[Gln1652*]; [Gln1709*] | Sur: no SNAP Rad: reduced SNAP+SNCV | Tib: reduced CMAP+MNCV Uln: reduced MNCV | not evoked LE | +, pancerebellar | - | + | + | + | + | - |
patients with 2
SACS
variants of unknown significance
| |||||||||||
#10 | p.[Thr458Ile]; [Thr458Ile] | Sur: normal | Tib: normal | normal UE+LE | slight vermal atrophy, herniation of tonsils | + | - | - | - | - | + |
#11 | p.[Thr458Ile]; [Val995Phe] | Sur: red SNAP Rad: red SNAP | Tib: red CMAP | prolonged UE+LE | +, pancerebellar | - | - | - | - | + | + |