Table 1.
Summary of all the main clinical and molecular features of the patients recruited.
| #ID | Sex | Age | AaO | AaD | Familial | Novel | Nucleotide | Predicted protein effect | PVS1 PM4 |
MAF (gnomAD) |
PM2 | PP2 | Revel score | PP3 | Domain* | PM1 | PM5 | PP5 | ALP (UI) | Normal range (UI) | Vit B6 (7–18 ng/l) | PP4 | Clinical interpretation |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| #1 | F | 45 | 20 | 41 | NA | No | c.668G>A | p.(Arg223Gln) | / | 1.6 × 10-5 | Mod | Supp | 0.97 | Supp | CBS | Mod | Mod | Supp | 21 | 35-107 | 44.4 | Supp | LP |
| #2 | F | 64 | 37 | 58 | NA | Yes | c.1415A>G | p.(His472Arg) | / | Absent | Mod | Supp | 0.87 | Supp | HI | Mod | / | / | 8 | 40-150 | 33.5 | Supp | LP |
| #3 | F | 75 | 66 | 71 | NA | Yes | NA | del exon 2 | vs | Absent | Mod | / | / | / | / | / | / | / | 31 | 40-150 | 48.7 | / | LP |
| #4 | F | 52 | 45 | 46 | Yes | No | c.657G>T | p.(Met219Ile) | / | 1.6 × 10-5 | Mod | Supp | / | / | CBS | Mod | / | Supp | 19 | 40-150 | 52.1 | Supp | LP |
| #5 | F | 6 | NA | 15 months | Yes | No | c.571G>A c.963delG |
p.(Glu191Lys) p.(Lys322Argfs*44) |
/ vs |
2.4 × 10-3
Absent |
Mod Mod |
Supp / |
0.84 / |
Supp / |
AS B |
Mod NA |
Mod NA |
vs Supp |
20 | 156-369 | 383 | Supp | LP P |
| #6 | M | 62 | 49 | 56 | Yes | No | c.327C>A | p.(Asp109Glu) | / | Absent | Mod | Supp | 0.89 | Supp | AS | Mod | / | / | 21 | 46-116 | 48.9 | / | LP |
| #7 | F | 57 | 50 | 52 | Yes | No | c.262G>A | p.(Glu88Lys) | / | Absent | Mod | Supp | 0.77 | Supp | HI | Mod | / | / | 25 | 30-120 | 27 | Supp | LP |
| #8 | M | 9 | 2.5 | 5 | Yes | No | c.1172G>A | p.(Arg391His) | / | 1.1 × 10-5 | Mod | Supp | 0.93 | Supp | HI/CD | Mod | Supp | Supp | 81 | 156-369 | 580 | Supp | LP |
| #9 | F | 59 | NA | 54 | NA | No | c.327C>A | p.(Asp109Glu) | / | Absent | Mod | Supp | 0.89 | Supp | AS | Mod | / | / | 21 | 40-150 | 73.6 | / | LP |
| #10 | F | 27 | 10 | 22 | Yes | No Yes |
c.407G>A c.870C>G |
p.(Arg136His) p.(Phe290Leu) |
/ / |
1.2 × 10-4
Absent |
Mod Mod |
Supp Supp |
0.7 0.82 |
Supp Supp |
AS CBS |
Supp Supp |
Mod / |
Supp Supp |
18 | 40-150 | 82 | Supp | LP VUS |
| #11 | F | 73 | 38 | 68 | NA | Yes | c.1171insC | p.(Arg391Profs*14) | vs NA |
4 × 10-6 | Mod | / | / | / | HI/CD | / | NA | Supp | 27 | 35-104 | 65.2 | / | P |
| #12 | F | 38 | 30 | 31 | NA | No | c.892G>A | p.(Glu298Lys) | / | 2.1 × 10-5 | Mod | Supp | 0.93 | Supp | CBS | Mod | / | / | 25 | 40-150 | 21.4 | Supp | LP |
| #13 | F | 57 | NA | 53 | Yes | Yes | c.1573T>C | p.(*525Argextfs*11) | NA mod |
4.1 × 10-6 | Mod | / | / | / | GPI | / | / | / | 41 | 45-117 | 23.6 | Supp | VUS |
| #14 | F | 48 | 12 | 43 | Yes | No | c.283G>A | p.(Val95Met) | / | 3.3 × 10-5 | Mod | Supp | 0.76 | Supp | AS | Mod | / | / | 36 | 40-150 | 30.2 | Supp | LP |
| #15 | F | 70 | 56 | 67 | NA | Yes | c.800A>C | p.(His267Pro) | / | Absent | Mod | Supp | 0.76 | Supp | CBS | / | / | / | 33 | 53-141 | 55 | Supp | VUS |
| #16 | M | 68 | 63 | 65 | NA | No | c.668G>A | p.(Arg223Gln) | / | 1.6 × 10-5 | Mod | Supp | 0.96 | Supp | CBS | Mod | / | / | 41 | 45-117 | 45 | Supp | LP |
| #17 | F | 37 | 14 | 35 | NA | Yes | c.928dupT | p.(Ser310Profs*28) | vs NA |
Absent | Mod | / | / | / | NA | / | / | / | 24 | 33-98 | 88 | Supp | LP |
| #18 | F | 51 | NA | 49 | NA | Yes | c.250G>A | p.(Glu84Lys) | / | Absent | Mod | Supp | 0.9 | Supp | HI | Mod | / | / | 19 | 42-98 | 235 | / | LP |
| #19 | F | 61 | 17 | 60 | NA | Yes | c.855C>G | p.(Tyr85*) | vs NA |
Absent | Mod | / | / | / | HI | / | / | / | 23 | 35-104 | 99.5 | Supp | LP |
| #20 | F | 65 | 55 | 64 | NA | No | c.98C>T | p.(Ala33Val) | / | 1.4 × 10-5 | Mod | Supp | 0.87 | Supp | N-ter α-helix |
Supp | NA | Supp | 38 | 45-117 | 46.4 | Supp | LP |
| #21 | M | 5 | 20 ds | 30 days | Yes | No | c.620A>C | p.(Gln207Pro) | / | Absent | Mod | Supp | 0.98 | Supp | NA | Mod | NA | Supp | 147 | 90-345 | / | / | LP |
| #22 | M | 5 | 1 y | 2 years 10 months | Yes | No | c.542C>T | p.(Ser181Leu) | / | 4 × 10-5 | Mod | Supp | 0.79 | Supp | NA | Mod | Mod | Supp | 129 | 141.8-336.4 | / | / | LP |
| #23 | M | 66 | 10 | 65 | NA | No | c.262G>A | p.(Glu88Lys) | / | Absent | Mod | Supp | 0.77 | Supp | HI | Mod | / | / | 63 | 50-136 | / | / | LP |
| #24 | M | 67 | 50 | 63 | / | / | / | / | / | / | / | / | / | / | / | / | / | / | 30 | 40-150 | 36.1 | / | / |
| #25 | M | 70 | 50 | 68 | / | / | / | / | / | / | / | / | / | / | / | / | / | / | 28 | 30-120 | 47.9 | / | / |
| #26 | M | 70 | 60 | 63 | / | / | / | / | / | / | / | / | / | / | / | / | / | / | 36 | 40-150 | 23.3 | / | / |
| #27 | M | 81 | NA | 74 | / | / | / | / | / | / | / | / | / | / | / | / | / | / | 41 | 45-117 | 23.4 | / | / |
| #28 | F | 91 | 70 | 86 | / | / | / | / | / | / | / | / | / | / | / | / | / | / | 36 | 40-150 | 58.5 | / | / |
| #29 | F | 39 | 13 | 34 | / | / | / | / | / | / | / | / | / | / | / | / | / | / | 3,4 | 8.5-14.3 | 52.2 | / | / |
| #30 | M | 62 | 40 | 59 | / | / | / | / | / | / | / | / | / | / | / | / | / | / | 39 | 40-150 | 32 | / | / |
| #31 | M | 45 | 30 | 39 | / | / | / | / | / | / | / | / | / | / | / | / | / | / | 35 | 40-150 | 32 | / | / |
| #32 | M | 65 | 53 | 59 | / | / | / | / | / | / | / | / | / | / | / | / | / | / | 38 | 40-150 | 33.5 | / | / |
| #33 | M | 73 | NA | 69 | / | / | / | / | / | / | / | / | / | / | / | / | / | / | 25 | 30-120 | 25.3 | / | / |
For all the variants, pathogenicity criteria conferred by Franklin and the final interpretation according to the ACCMG guidelines were given: for some variants, the final interpretation switched from VUS to LP or from LP to P, in the presence of the specific phenotype criteria (PP4), that was bestowed only for patients having the TNSALP lower and VitB6 higher, than the normal range. AaO = age at onset; AaD = age at diagnosis; * for each variant, the corresponding domain was obtained from ref (1), ref (3), and ref (8); AS, active site; B, basis; CBS, calcium binding site; CD, crown domain; GPI, glycosylphosphatidylinositol anchor; HI, homodimer interface; NA, not available; NP, not present; Mod, moderate; Supp, supporting; vs, very strong.