Table 1.
Clinical and molecular characterization of the study cohort
| Patient ID | AP4-HSP subunit | Allele 1 | Allele 2 |
CADD PHRED
score |
ACMG classification a | Sex | Age | SPRS | 4-FMS | AP-4-HSP core features | ATG9A ratio |
|---|---|---|---|---|---|---|---|---|---|---|---|
| P−/−_01 | AP4B1 | c.1345A>T (p.Arg449Ter) (Nonsense) | c.1160_1161delCA (p.Thr387ArgfsTer30) (Frameshift) | 36/33 | Pathogenic/pathogenic | M | 3 y 11 m | 18 | 2 | 9/9 | 1.65 |
| P−/−_02 | AP4B1 | c.530_531insA (p.Asn178GlufsTer20) (Frameshift) | c.114-2A>C p.? (Splice site) | 32/34 | Pathogenic/pathogenic | F | 5 y 3 m | 15 | 3 | 7/9 | 1.59 |
| P−/−_03 | AP4B1 | c.1216C>T (p.Arg406Ter) (Nonsense) | c.1328T>C (p.Leu443Pro) (Missense) | 41/28.1 | Pathogenic/uncertain significance | F | 4 y 11 m | 35 | 4 | 8/9 | 1.44 |
| P−/−_04 | AP4B1 | c.1216C>T (p.Arg406Ter) (Nonsense) | c.1328T>C (p.Leu443Pro) (Missense) | 41/28.1 | Pathogenic/uncertain significance | F | 4 y 10 m | 22 | 3 | 8/9 | 1.70 |
| P−/−_05 | AP4B1 | c.114-2A>C p.? (Splice site) | c.114-2A>C p.? (Splice site) | 34/34 | Pathogenic/pathogenic | F | 7 y 5 m | 32 | 3 | 8/9 | 1.71 |
| P−/−_06 | AP4B1 | c.617G>A (p.Arg206Gln) (Missense) | c.617G>A (p.Arg206Gln) (Missense) | 33/33 | Likely pathogenic/likely pathogenic | M | 4 y 8 m | 22 | 3 | 8/9 | 1.39 |
| P−/−_07 | AP4B1 | c.1160_1161delCA (p.Thr387ArgfsTer30) (Frameshift) | c.1160_1161delCA (p.Thr387ArgfsTer30) (Frameshift) | 33/33 | Pathogenic/pathogenic | M | 8 y 10 m | 41 | 4 | 9/9 | 1.55 |
| P−/−_08 | AP4B1 | c.664delC (p.Leu222CysfsTer31) (Frameshift) | c.1177C>T (p.Arg393Ter) (Nonsense) | 28.9/40 | Pathogenic/pathogenic | M | 1 y 9 m | NA | 4 | 8/9 | 1.75 |
| P−/−_09 | AP4B1 | c.1608_1609insCA (p.Lys537GlnfsTer18) (Frameshift) | c.1608_1609insCA (p.Lys537GlnfsTer18) (Frameshift) | 32/32 | Pathogenic/pathogenic | M | 7 y 2 m | 22 | 2 | 8/9 | 1.63 |
| P−/−_10 | AP4M1 | c.916C>T (p.Arg306Ter) (Nonsense) | c.916C>T (p.Arg306Ter) (Nonsense) | 39/39 | Pathogenic/pathogenic | F | 31 y 11m | NA | 4 | 8/9 | 1.36 |
| P−/−_11 | AP4M1 | c.218dupA (p.Asn73LysfsTer43) (Frameshift) | c.851A>C (p.Tyr284Ser) (Missense) | 24.5/29.5 | Pathogenic/Uncertain Significance | M | 9 y 1 m | 41 | 4 | 9/9 | 1.50 |
| P−/−_12 | AP4M1 | c.916C>T (p.Arg306Ter) (Nonsense) | c.694dupG (p.Glu232GlyfsTer21) (Frameshift) | 39/33 | Pathogenic/pathogenic | M | 18 m | 29 | 4 | 9/9 | 1.46 |
| P−/−_13 | AP4M1 | c.1025 + 2dupT p.? (Splice site) | c.205A>C (p.Thr69Pro) (Missense) | 34/22.4 | Uncertain significance/uncertain significance | M | 5 y 10 m | 0 | 2 | 6/9 | 1.37 |
| P−/−_14 | AP4S1 | c.138 + 3_138 + 6delAAGT p.? (Splice site) | c.138 + 3_138 + 6delAAGT p.? (Splice site) | 33/33 | Pathogenic/pathogenic | F | 4 y 11 m | NA | 3 | 7/9 | 1.39 |
| P−/−_15 | AP4S1 | c.294 + 1G>T p.? (Splice site) | c.294 + 1G>T p.? (Splice site) | 35/35 | Pathogenic/pathogenic | M | 3 y 6 m | 19 | 3 | 9/9 | 1.52 |
| P−/−_16 | AP4S1 | c.289C>T (p.Arg97Ter) (Nonsense) | c.289C>T (p.Arg97Ter) (Nonsense) | 50/50 | Pathogenic/pathogenic | F | 4 y 2 m | 22 | 2 | 9/9 | 1.64 |
| P−/−_17 | AP4S1 | c.49dupT (p.Ser17PhefsTer2) (Frameshift) | c.49dupT (p.Ser17PhefsTer2) (Frameshift) | 30/30 | Pathogenic/pathogenic | F | 12 y 9 m | NA | 3 | 8/9 | 1.51 |
| P−/−_18 | AP4S1 | c.49dupT (p.Ser17PhefsTer2) (Frameshift) | c.238_239insG (p.Ile80SerfsTer3) (Frameshift) | 30/33 | Pathogenic/pathogenic | F | 17 y 1 m | 24 | 3 | 8/9 | 1.56 |
| PVUS/VUS_01 | AP4B1 | c.1024G>T (p.Asp342Tyr) (Missense) | c.868C>T (p.Arg290Cys) (Missense) | 28.6/25.5 | Uncertain significance/uncertain significance | F | 3 y 0 m | NA | 4 | 3/9 | 1.16 |
| PVUS/VUS_02 | AP4B1 | c.409A>G (p.Arg137Gly) (Missense) | c.409A>G (p.Arg137Gly) (Missense) | 24.4/24.4 | Uncertain significance/uncertain significance | F | 41 y 3 m | NA | 2 | 1/8 | 1.27 |
F, female; M, male; m, months; NA, not available; SPRS, Spastic Paraplegia Rating Scale; y, years. Reference sequences: AP4B1: NM_001253852.3; AP4M1: NM_004722.4; AP4E1: NM_007347.5; AP4S1: NM_007077.4.
a
Classification of variants based on ACMG criteria using VarSome (Kopanos et al., 2019). CADD PHRED scores were computed using version 1.6 (https://cadd.gs.washington.edu/score).27