Table 2.
PLS cases with a genetic variant
| Genetic information | Clinical information | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Gene | Variant (RNA/protein/ splicing change) | Classification (ACMG) | Inheritance | gnomAD allele count |
ACMG details | Sex | AoO/ AoD (y) |
DD (y) | BS | UU | Sensory symptoms | Non-motor symptoms | Family history | |
| 1 | C9orf72 | > 30 repeats (pathogenic > 30) | Pathogenic | Heterozygous | NA | NA | M | 39/45 | 17.2* | + | + | Numbness of both feet | PBA | Niece of father had ALS |
| 2 | C9orf72 | > 30 repeats (pathogenic > 30) | Pathogenic | Heterozygous | NA | NA | M | 71/77 | 10.8 | + | Unk | – | PBA, difficulty remembering names and people from the past, short term memory loss | – |
| 3 | SPAST | whole gene deletion | Pathogenic | Heterozygous | NA | NA | F | 31/35 | 42 | – | – | – | Pes cavus and hammer toes | Unk |
| 4 |
SPG11 SPG11 |
r.spl c.7000-2del p.(Gln2301*) |
Pathogenic Pathogenic |
Heterozygous Heterozygous |
– – |
PVS1, PM2, PM3 PVS1, PM2, PM3 | F | 73/75 | 9.1 | – | + | – | – | – |
| 5 | SPG7 | p.(Leu78*) | Pathogenic | Homozygous | 112/282546 | PVS1, PM3, | F | 31/39 | 37.3* | – | – | – | – | – |
| 6 | TBK1 | p.(Gly217Arg) | Pathogenic | Heterozygous | – | PS3, PS4, PP3 | F | 66/67 | 6.2 | – | – | – | PBA | Son walking problems |
| 7 | TBK1 | p.(Gly217Arg) | Pathogenic | Heterozygous | – | PS3, PS4, PP3 | M | 75/77 | 5.2 | + | + | – | PBA, pes cavus | Pes cavus and hammer toes |
| 8 | FIG4 | p.(Ile41Thr) | L Pathogenic (recessive) | Heterozygous | 284/282242 | PS3, PM3, PP3 (recessive) | M | 52/57 | 9.5 | – | + | – | – | – |
| 9 | NEFL | p.(Thr88Pro) | L Pathogenic | Heterozygous | – | PS4, PP1, PP3 | M | 53/56 | 11.7* | – | – | – | EMG: axonal sensorimotor polyneuropathy | – |
| 10 |
SPG7 SPG7 |
p.(Ala510Val) p.(Ile743Thr) |
L Pathogenic L Pathogenic |
Heterozygous Heterozygous |
820/282858 14/282720 |
PS4, PM3, PP1, PP3 PS4, PM3, PP1, PP3 | M | 37/40 | 31.5 | – | – | – | PBA | Unk |
| 11 | TBK1 | r.spl c.87 G > A | L Pathogenic | Heterozygous | – | PVS1, PM2 | F | 62/65 | 4.3 | + | + | – | PBA, prosopagnosia | – |
| 12 | ABCD1 | p.(Glu421Lys) | VUS | Hemizygous | 1/183147 | PM2 | M | 46/47 | 9.8 | + | – | – | – | – |
| 13 | ALDH18A1 | p.(Arg732Cys) | VUS | Heterozygous | 2/282722 | PP3 | M | 60/61 | 7.9* | – | – | Numb right foot | – | – |
| 14 | ANG | p.(His37Arg) | VUS | Heterozygous | 3/251494 | PP3 | M | 49/57 | 19.1* | + | – | – | – | – |
| 15 | ANXA11 | p.(Val352Met) | VUS | Heterozygous | 6/251416 | PP3 | M | 38/44 | 25.1* | – | + | – | – | – |
| 16 | ATXN2 | 32 repeats (normal < 32; pathogenic > 34) | VUS | Heterozygous | NA | NA | F | 71/74 | 9.9 | – | – | – | PBA | – |
| 17 | CHMP2B | p.(Met102Val) | VUS | Heterozygous | 1/31388 | PP3 | M | 58/59 | 19.3 | – | – | – | FTD | – |
| 18 | DCTN1 | p.(Asp748Glu) | VUS | Heterozygous | 5/282770 | PP3 | M | 61/64 | 11.1* | + | + | – | PBA | – |
| 19 | ERBB4 | p.(Arg484Lys) | VUS | Heterozygous | 2/282866 | PP3 | F | 51/52 | 14.2* | – | – | – | – | – |
| 20 | FA2H | p.(Val309Ile) | VUS | Homozygous | 60/282546 | PP3 | M | 58/63 | 8.5 | + | – | – | – | – |
| 21 | FUS | p.(Gln179His) | VUS | Heterozygous | – | PM2, PP3 | M | 65/71 | 24.8* | – | – | – | – | – |
| 22 | FUS | p.(Gly474Arg) | VUS | Heterozygous | 1/250650 | PP3 | F | 62/67 | 11.7 | – | + | Numbness and lowered vibration sense left leg | – | – |
| 23 | NEK1 | p.(Gln95*) | VUS | Heterozygous | 1/248912 | PVS1, | F | 69/71 | 5.8 | + | – | – | – | – |
| 24 | NEK1 | p.(Ser1047Leu) | VUS | Heterozygous | 7/280336 | PP3 | M | 77/81 | 13.8 | + | – | – | PBA | – |
| 25 | NIPA1 | p.(Ala86Gly) | VUS | Hemizygous | – | PM2, PP3 | M | 39/49 | 10.3 | – | – | – | – | – |
| 26 | OPTN | p.(Leu410Pro) | VUS | Heterozygous | 3/250750 | PP3 | M | 47/48 | 9* | + | – | – | CTS bilaterally + ulnar neuropathy left (both improved after CTS treatment) | – |
| 27 | PPP2R2B | 46 repeats (normal < 33; pathogenic > 50) | VUS | Heterozygous | NA | NA | F | 56/61 | 15.5* | – | Unk | Numbness of distal limbs | PBA | – |
| 28 | SETX | p.(His227Leu) | VUS | Heterozygous | – | PM2, PP3 | M | 83/87 | 7.8 | + | – | – | – | – |
| 29 | UBAP1 | p.(His430Tyr) | VUS | Heterozygous | 3/282828 | PP3 | M | 64/65 | 12.3 | – | – | Tingling of distal limbs, numbness during walking | Unk | – |
| 30 | VCP | p.(Ile114Val) | VUS | Heterozygous | 20/282856 | PP3 | M | 51/53 | 13.6* | – | – | – | Pes cavus and hammer toes | – |
| 31 | ZFYVE27 | r.(spl?) c.912 + G > A | VUS | Heterozygous | – | PM2, PP3 | M | 52/68 | 29.8 | + | + | – | PBA | – |
Evidence of pathogenicity was determined using the ACMG criteria for classifying pathogenic variants
PVS1: very strong evidence of pathogenicity (null variant in a gene where loss of function is a known mechanism of disease); PS3: strong evidence of pathogenicity (well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product; PS4: strong evidence of pathogenicity (the prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls); PM2: moderate evidence of pathogenicity (absent from controls or at extremely low frequency if recessive); PM3: moderate evidence of pathogenicity (for recessive disorders, detected in trans with a pathogenic variant); PM4: moderate evidence of pathogenicity (protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants; PP1: supporting evidence of pathogenicity (co-segregation with disease in multiple affected family members in a gene definitively known to cause a disease); PP3: supporting evidence of pathogenicity (multiple lines of computational evidence support a deleterious effect on the gene or gene product)
ACMG American College of Medical Genetics and Genomics, AoD age of diagnosis, AoO age of onset, BS Bulbar symptoms, DD disease duration (was date of onset– date of death, for patients that are still alive* in our database this was date of diagnosis—26-8-2022), EMG electromyography, F female, FTD frontotemporal dementia, L likely, M male, NA not applicable, PBA pseudobulbar affect (emotional inhibition, inappropriate laughing and/or crying and/or yawning), RNA ribonucleic acid, Unk unknown, UU urinary urgency, VUS variant of unknown significance, y years, + present, − absent