Table 2.
Rare variants found in APP, PSEN1, PSEN2, MAPT, GRN, PRNP in 141 LOAD cases and 179 controls
| Variant interpretation | Gene | Position | Nucleotide change | Aa change | Minor allele | status | SIFT/Polyphen | LOAD cases (n = 141) |
Comment | CONTROLS (n = 179) |
|||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Count (%) | (AAO–AAD) | Genotype | APOE | Count (%) | Genotype | APOE | |||||||||
| PROBABLE PATHOGENIC* | |||||||||||||||
| PSEN1 | 14:73653583 | c.503T>C | p.I168T | C | novel | possibly-damaging | 1 (0.7) | 86y-94y | T/C | ε2ε4 | p.I168del reported in FAD | 0 | - | - | |
| PSEN2 | 1:227076673 | c.710 C>T | p.A237V | T | rs200670135 | possibly-damaging | 1 (0.7) | 87y-95y | C/T | ε3ε3 | Homologous residue in PSEN1 (p.A231) | 0 | - | - | |
| LIKELY RARE BENIGN POLYMORPHISMS | |||||||||||||||
| APP | 21:27423376 | c.602 C>T | p.A201V | T | rs149995579 | tolerated | 0 | - | - | - | EXON 5 | 1 (0.5) | C/T | ε3ε4 | |
| 21:27326979 | c.1612 T>C | p.Y538H | C | novel | possibly-damaging | 1 (0.7) | 69y-77y | T/C | ε3ε4 | EXON 13 | 0 | - | - | ||
| 21:27326907 | c.1684 G>A | p.V562I | A | rs199586073 | tolerated | 0 | - | - | - | EXON 13 | 1 (0.5) | G/A | ε3ε3 | ||
| 21:27284167 | c.1795 G>A | p.E599K | A | rs140304729 | possibly-damaging | 0 | - | - | - | EXON 14 | 1 (0.5) | G/A | ε3ε4 | ||
| PSEN2 | 1:227071448 | c.184 C>T | p.R62C | T | rs150400387 | possibly-damaging | 1 (0.7) | 83y-91y | C/T | ε3ε3 | N-Terminal | 0 | - | - | |
| 1:227071449 | c.185 G>A | p.R62H | A | rs58973334 | tolerated | 1 (0.7) | 75y-89y | G/A | ε3ε3 | N-Terminal | 0 | - | - | ||
| 1:227073271 | c.389 C>T | p.S130L | T | rs63750197 | possibly-damaging | 1 (0.7) | 69y-77y | C/T | ε3ε3 | 1 (0.5) | C/T | ε2ε2 | |||
| 1:227083249 | c.1316 A>C | p.D439A | C | rs63750110 | possibly-damaging | 1 (0.7) | 75y-89y | A/C | ε3ε3 | C-Terminal | 1 (0.5) | A/C | ε3ε3 | ||
| GRN | 17:42428954 | c.970 G>A | p.A324T | A | rs63750541 | tolerated | 0 | - | - | - | 2 (1.1) | G/A | ε3ε3, ε3ε2 | ||
| 17:42429497 | c.1294 C>T | p.R432C | T | rs63750130 | tolerated | 1 (0.7) | 94y | C/T | ε3e4 | 0 | - | - | |||
| 17:42429500 | c.1297 C>T | p.R433W | T | rs63750412 | possibly-damaging | 1 (0.7) | 69y-81y | C/T | ε4ε4 | 0 | - | - | |||
| 17:42430128 | c.1744 G>A | p.A582T | A | rs72824737 | tolerated | 0 | - | - | - | 1 (0.5) | G/A | ε3ε3 | |||
| MAPT | 17:44068824 | c.115-2A>T | frameshift | T | novel | possibly-damaging | 1 (0.7) | 81y-89y | A/T | ε4ε4 | 0 | - | - | ||
| 17:44060841 | c.671 T>G | p.V224G | G | rs141120474 | possibly-damaging | 2 (1.4) | 74y-82y; 88y- | T/G | ε2ε3; ε2ε3 | 1 (0.5) | T/G | ε3ε2 | |||
| 17:44060807 | c.637 G>A | p.G213R | A | rs76375268 | possibly-damaging | 2 (1.4) | 74y-82y; 75y- | G/A | ε3ε4; ε3ε3 | 0 | - | - | |||
| 17:44060769 | c.599 G>A | p.G200E | A | novel | possibly-damaging | 0 | - | - | - | 1 (0.5) | G/A | ε3ε3 | |||
| PRNP | 20:4680266 | c.400 A>G | p.M134V | G | novel | possibly-damaging | 0 | - | - | - | 1 (0.5) | A/G | ε3ε2 | ||
| LIKELY LOW FREQUENCY AND COMMON BENIGN POLYMORPHISMS | |||||||||||||||
| PRNP | 20:4680094-4680118 | delACAGCCTCATGGTGGTGGCTGGGG | delACAGCCTCATGGTGGTGGCTGGGG | rs138688873 | possibly-damaging | 2 (1.4) | 80y-88y; 76y-83y | delACAGCCTCATGGTGGTGGCTGGGG | ε3ε3; ε3ε3 | 0 | - | - | |||
| 20:4680251 | c.385 A>G | p.M129V | G | rs1799990 | tolerated | 64 (45) | A/G | 68 (38) | A/G | ||||||
Rare variants in causative genes for the monogenic forms of neurodegenerative dementias (AD, FTD, PSP, CBD, CJD): amyloid precursor protein, APP (NM_000484.3); presenilins 1and 2, PSEN1 (NM_000021.3) and PSEN2 (NM_000447.2); progranulin, GRN (NM_002087.2); microtubule associated protein Tau, MAPT (NM_001123066.3); prion protein, PRNP (NM_000311.3).
Key: AD, Alzheimer’s disease; AAD, age at death; AAO, age at onset; CJD, Creutzfeldt-Jakob disease; FAD, familial Alzheimer’s disease; FTD, frontotemporal dementia; PSP, progressive supranuclear palsy; Aa, amino acid.
* Classification based on the algorithm proposed by Guerreiro et al., 2010a.