Table 3.
MS Phenocopy Variants Selected for Phase 1 and Phase 2 Replication
| Genetic Variant | Number of Individuals Carrying a Heterozygous Mutation | Minor Allele Frequency (%)a | Risk vs ExAC EUR | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Discovery Cohort (WGS) | Phase 1 Replication (OpenArray) | Phase 2 Replication (targeted typing) | ||||||||||||
| Gene | Variantb | Disorder (inheritance)c | 38 PPMS | 81 CTRLS | 411PPMS | 460 RMS | 335 PPMS | 2589 RMS | 1000 CTRLS | All PPMS | All RMS | All CTRLS | ExAC EUR | RR for PPMS |
| KIF5A | p.A361V | SPG10 (AD) | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0.064 | 0.016 | 0.000 | 0.003 | 23.3 |
| TSC2 | p.E75K | TSd (AD) | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0.064 | 0.000 | 0.000 | 0.019 | 3.3 |
| MLC1 | p.P92S | MLC (AR) | 1 | 0 | 0 | 0 | 0 | 4 | 0 | 0.064 | 0.066 | 0.000 | 0.034 | 1.9 |
| REEP1 | c.606 +43G>T | SPG31 (AD) | 1 | 0 | 2 | 0 | 0 | 2 | 2 | 0.191 | 0.033 | 0.093 | 0.115 | 1.7 |
| SCN9A | p.W1538R | PE (AD) | 1 | 0 | 6 | 3 | Not selected for Phase 2: | 0.67 | 0.33 | 0.00 | 0.173 | 3.9 | ||
| HPD | p.I335M | TYRSN3 (AR) | 1 | 0 | 3 | 3 | Variant was found in at least | 0.33 | 0.33 | 0.00 | 0.158 | 2.1 | ||
| CACNA1A | p.P897R | EA2 (AD) | 1 | 0 | 1 | 2 | one RMS patient in Phase 1. | 0.22 | 0.22 | 0.00 | 0.141 | 1.6 | ||
| DCTN1 | p.T1249I | ALS (AD) | 1 | 0 | 3 | 4 | 0.22 | 0.43 | 0.00 | 0.416 | 0.5 | |||
| D2HGDH | p.A426T | D‐2‐HGA (AR) | 3 | 0 | 7 | 3 | 0.89 | 0.33 | 0.00 | 1.101 | 0.8 | |||
| ADAR | p.P193A | AGS (AR, AD) | 1 | 0 | 1 | 1 | 0.22 | 0.11 | 0.00 | 0.281 | 0.8 | |||
| NOTCH3 | p.S497L | CADASIL (AD) | 2 | 0 | 7 | 4 | 0.67 | 0.43 | 0.00 | 1.395 | 0.5 | |||
| SLC6A5 | p.T690T | HKPX3d (AD) | 1 | 0 | 0 | 4 | 0.11 | 0.43 | 0.00 | 0.271 | 0.4 | |||
| NF1 | p.D176E | NF1 (AD) | 1c | 0 | 2 | 5 | Not selected for Phase 2: | 0.24 | 0.54 | 0.00 | 0.512 | NA | ||
| TSC2 | p.L1423L | TSd AD) | 1c | 0 | 0 | 0 | CGI genotypes not | 0.00 | 0.00 | 0.00 | 0.423 | |||
| LRRK2 | p.E334K | PD (AD) | 1c | 0 | 0 | 0 | validated on OA | 0.00 | 0.00 | 0.00 | 0.484 | |||
Minor allele frequencies (MAFs) are calculated for 784 PPMS, 3,049 RMS, and 1,081 control subjects for the top four candidate variants. For all other variants, MAF is calculated for 449 PPMS, 460 RMS, and 81 control subjects. The ExAC European (including Finnish) cohort was used as the reference to calculate relative risk for candidate variants.
“c” denotes coding DNA sequence position; “p” denotes protein amino acid position. Only the variant corresponding to the primary transcript according to ExAC is provided.
Phenocopy disorder abbreviations: SPG = spastic paraplegia; TS = tuberous sclerosis; MLC = megalencephalic leukodystrophy with subcortical cysts; PE = primary erythromelalgia; TYRSN3 = tyrosinemia type 3; EA2 = episodic ataxia 2; ALS = amyotrophic lateral sclerosis; D‐2‐HGA = D‐2‐hydroxyglutaric aciduria; AGS = Aicardi‐Goutières syndrome; CADASIL = cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy; HKPX3 = hyperekplexia 3; NF1 = neurofibromatosis type 1; PD = Parkinson's disease.
These variants were not validated during Phase 1 replication genotyping.
These variants have not yet been reported to be pathogenic in this disorder.