Table 4.
Details on XPR1 variants and phenotype of variant carriers
| Family number | Case ID | Study | Novel variant or ref. | ACMG class | Variant type | cDNA | Protein | Domain (missense) or predicted protein consequences | gnomAD | Mutation Taster | Polyphen2 | SIFT | Ethnicity | Sex | Clinical summary | AAO | Family History | CT scan |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 40 | EXT 1003 001 | France | 23 [same patient] | 5 | Missense | c.260T>C | p.(Leu87Pro) | SPX domain | Absent | DC (1) | PD (1) | D (0) | Caucasian | M | Dysarthria with parkinsonian and cerebellar features, concentration deficit, mild executive dysfunction, micrography, parkinsonism, anxiety | 37 | Positive | Pa, Pu, Ca, T, D, Ve, WM, Co |
| 41 | EXT 1187 001 | France | 22 | 5 | Missense | c.434T>C | p.(Leu145Pro) | SPX domain | Absent | DC (1) | PD (1) | D (0.01) | Caucasian | M | Extrapyramidal syndrome, cognitive impairment, dysarthria, behavioral disturbances | 29 | Positive | Pa, Pu, Ca, T, D, Co (MRI) |
| EXT 1187 002 | F | Bradykinesia, psychomotor slowing | 38 | Pa, Pu, Ca, T, D, Co | ||||||||||||||
| 42 | IT-PFBC- 11 | Italy | Novel | 4 | Missense | c.697A>T | p.(Thr233Ser) | Outside from SPX domain | 8.133e−6 (1.795e−5, NFE) | DC (0.99) | PossD (0.885) | D (0.03) | Caucasian | F | Mild Cognitive Impairment | 81 | Negative | Pu, Pa |
| 43 | IT-PFBC-12 | Italy | Novel | 4 | Missense | c.697A>T | p.(Thr233Ser) | Outside from SPX domain | 8.133e−6 (1.795e−5, NFE) | DC (0.99) | PossD (0.885) | D (0.03) | Caucasian | F | Vertigo | 50 | Negative | Pa, Pu |
| 44 | ROU 5059 001 | France | Novel | 4 | Missense | c.1375C>T | p.(Arg459Cys) | Outside from SPX domain | Absent | DC (1) | PD (1) | D (0) | Caucasian | M | l-Dopa-responsive extrapyramidal syndrome, mild intellectual disability | 55 | Negative | Pa, Pu, Ca, D |
| 45 | EXT 1219 001 | France | Novel | 3 | Missense | c.1855A>G | p.(Asn619Asp) | Outside from SPX domain | Absent | DC (1) | PD (1) | D (0) | Caucasian | M | Sudden deafness, mild cerebellar syndrome | 69 | Positive | Pa, Pu, Ca, D, T |
ACMG class: 5—pathogenic, 4—likely pathogenic, 3—variant of unknown significance. Novel variant refers to variants that have not been previously reported in PFBC patients. gnomAD frequency, in parentheses is the maximal subpopulation frequency for Non-Finnish Europeans (NFE). Family history was considered positive if at least one first-degree relative exhibited at least one neuropsychiatric symptom by interview
Variants were submitted to the https://coppolalab.ucla.edu/lovd_pfbc/genes/XPR1 database. Reference sequence: NM_004736.3
Associated references: [22, 23]
AAO age at onset, Pa pallidum, Pu putamen, Ca caudate nuclei, T thalamus, D dentate nuclei, Co cerebral cortex, WM subcortical white matter, NA not available, DC disease causing, PossD possibly damaging, PD probably damaging, T tolerated, D deleterious