Table 1.
Details on SLC20A2 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | EXT 1291 001 | France | Novel | 5 | Nonsense | c.149T>G | p.(Leu50Ter) | Premature stop codon | Absent | NA | NA | NA | Caucasian | F | Psychosis and extrapyramidal syndrome | 63 | Negative | Pa, Pu, WM, D |
| 2 | IT-PFBC-7 | Italy | 32 | 4 | Missense | c.212G>A | p.(Arg71His) | Phosphate transporter | Absent | DC (0.9) | PD (1) | D (0) | Caucasian | F | Asymptomatic | NA | Negative | Pa, Pu, Ca, T |
| 3 | EXT 878 001 | France | Novel | 3 | Predicted splicing | c.289+5G>A | p.? | Predicted loss of 5’ splicing donor site | Absent | NA | NA | NA | Caucasian | F | Pain, akinetic–rigid syndrome with tremor, gait disorder, and hypophonia | 72 | Negative | Pa, Pu, Ca, D, T, Co, WM, Ver |
| 4 | IT-PFBC-1 | Italy | Novel | 3 | Predicted splicing | c.290-8A>G | p.? | Predicted loss of 3’ splicing acceptor site | Absent | NA | NA | NA | Caucasian | F | Akinetic–rigid parkinsonism, LD responsive | 65 | Negative | Pa, Pu, D |
| 5 | EXT 1132 001 | France | Novel | 3 | Missense/ splicing? | c.290G>A | p.(Gly97Asp) | First base of exon 3; however, splicing tools predict a minor effect on splicing (MaxEntScan score change:-7%) | Absent | DC (1) | PD (1) | D (0.02) | Polynesian | M | Anxiety, depression, apathy, somatoform signs, and attention deficit | 18 | Positive | Pa, Pu, Ca, T, WM, Co |
| 6 | Proband | USA | 28,29 | 5 | Nonsense | c.338C>G | p.(Ser113Ter) | Premature stop codon | Absent | DC (1) | NA | NA | NA | F | NA | NA | Positive | NA |
| 7 | IT-PFBC-6 | Italy | 28 [same patient] | 5 | Nonsense | c.338C>G | p.(Ser113Ter) | Premature stop codon | Absent | DC (1) | NA | NA | Caucasian | M | Focal unilateral chorea (hand) | 53 | Negative | Pa, Pu, Ca, T, D |
| 8 | EXT 945 001 | France | Novel | 5 | Frameshift | c.382del | p.(Val128SerfsTer43) | Premature stop codon | Absent | NA | NA | NA | Caucasian | M | Cerebellar ataxia, dysarthria, memory impairment with dysexecutive signs, and depression | 76 | Negative | Pa, Pu, Ca, T, D, WM, Co, Ver |
| 9 | Proband | USA | Novel | 4 | Missense | c.541C>T | p.(Arg181Trp) | Phosphate transporter domain | 4.084e−6 (4.512e−5, NFE) | DC (0.99) | PD (0.995) | T (0.06) | Caucasian | M | Progressive involuntary movements, neuropathic pain, and chronic headache | 60 | Positive | Pa, Pu, Ca |
| Father | M | Asymptomatic | NA | Pa, Pu, Ca | ||||||||||||||
| 10 | ROU 375 004 (mother) | France | 6 | 5 | Missense | c.551C>T | p.(Pro184Leu) | Cytoplasmic | Absent | DC (1) | PD (0.98) | D (0.05) | Caucasian | F | Restless leg syndrome | 55 | Positive | Pa, Pu, Ca, T, D |
| ROU 375 003 (sister) | F | Asymptomatic (migraine) | NA | Pa, Pu, Ca, T | ||||||||||||||
| ROU 375 002 (sister) | F | Pyramidal signs | 26 | Pa, Pu, Ca, T, WM | ||||||||||||||
| ROU 375 001 (proband) | F | Asymptomatic (migraine) | NA | Pa, Pu, Ca, T | ||||||||||||||
| 11 | EXT 1146 001 | France | 7 | 4 | Missense | c.581A>G | p.(Asn194Ser) | Transmembrane | 1.446e−5 (1.556e−4, NFE) | DC (0.99) | B (0.155) | T | NA | M | Akinetic–rigid syndrome, tremor, cerebellar ataxia, dysexecutive signs, and memory impairment | 68 | Positive | Pa, Pu, Ca, D, T, Co, WM, Ver |
| 12 | EXT 1180 001 | France | Novel | 5 | Splicing | c.730+1G>T | p.? | Predicted skipping of exon 6 (in-frame) or use of alternative splice site | Absent | NA | NA | NA | Caucasian | F | Bradykinesia, tremor, and dysexecutive signs | 40 | Negative | Pa, Pu, T, D, Co |
| 13 | IT-PFBC- 5b (first cousin) | Italy | Novel | 5 | Nonsense | c.739C>T | p.(Gln247Ter) | Premature stop codon | Absent | DC (1) | NA | NA | Caucasian | F | Asymptomatic | NA | Positive | Pa, Pu, Ca, T, D |
| IT-PFBC-5a (proband) | M | Chorea, orofacial dyskinesia, depression, and cognitive decline | 65 | Pa, Pu, Ca, T, D, Co, WM | ||||||||||||||
| 14 | ROU 5028 001 | France | 30 | 5 | Nonsense | c.1158C>A | p.(Tyr386Ter) | Premature stop codon with evidence of nonsense- mediated decay | Absent | DC (1) | NA | NA | Caucasian | F | Asymptomatic (migraine) | NA | Positive | Pa, Pu, D, Co |
| 15 | EXT 1118 001 | France | 30 | 5 | Nonsense | c.1158C>A | p.(Tyr386Ter) | Premature stop codon with evidence of nonsense- mediated decay | Absent | DC (1) | NA | NA | Caucasian | M | Akinetic–rigid syndrome, orofacial dyskinesia and dystonia (induced by l-dopa), pyramidal signs, gait disorder, and hallucinations (induced by l-dopa) | 51 | Negative | Pa, Pu, Ca, D, T, Co, WM, Ver |
| 16 | 1B02BR | Brazil | Novel | 5 | Frameshift | c.1187dup | p.(Pro397AlafsTer18) | Premature stop codon | Absent | DC (1) | NA | NA | NA | F | Parkinsonism | NA | Positive | NA |
| 1B01BR | M | Stroke, aphasia, and parkinsonism | NA | NA | ||||||||||||||
| 17 | EXT 1083 001 | France | Novel | 5 | Nonsense | c.1207C>T | p.(Arg403Ter) | Premature stop codon | Absent | DC (1) | NA | NA | Caucasian | M | Akinetic–rigid syndrome | 65 | Negative | Pa, Pu, Ca, D, T, Co, WM, Ver |
| 18 | IT-PFBC-2 | Italy | 31 | 4 | Missense | c.1301C>G | p.(Ser434Trp) | Phosphate transporter domain | 3.228e−5 (6.663e−5, NFE) | DC (0.99) | PD (0.997) | D (0.00) | Caucasian | F | Parkinsonism and postural/kinetic tremor. Comorbid Down syndrome | 3 | Negative | Pa, Pu, D |
| 19 | EXT 1063 001 | France | Novel | 5 | Nonsense | c.1426G>T | p.(Glu476Ter) | Premature stop codon | Absent | DC (1) | NA | NA | Caucasian | M | Akinetic–rigid syndrome, bipolar disorder. Mild cerebellar ataxia | 44 | Positive | Pa, Pu, Ca, D, T, Co, WM, Ver |
| 20 | IT-PFBC-3 | Italy | Novel | 3 | Missense | c.1463A>G | p.(His488Arg) | Phosphate transporter | Absent | DC (0.99) | B (0.005) | T (0.83) | Caucasian | F | Subjective memory impairment, normal psychometry | 59 | Negative | Pa, Pu |
| 21 | Proband | USA | 3 | 5 | Missense | c.1492G>A | p.(Gly498Arg) | Phosphate transporter | Absent | DC (0.99) | PD (0.994) | D (0.00) | Caucasian | M | l-dopa-responsive parkinsonism, increased muscle tone and pain | NA | Negative | Pa, Pu, Ca, T |
| 22 | IT-PFBC-8a (proband) | Italy | 3 | 5 | Missense | c.1492G>A | p.(Gly498Arg) | Phosphate transporter | Absent | DC (0.99) | PD (0.994) | D (0.00) | Caucasian | M | Akinetic–rigid parkinsonism, dysarthria | 68 | Positive | Pa, Pu, Ca, T, D, Co, WM |
| IT-PFBC- 8b (daughter) | F | Asymptomatic | NA | Pa, Pu | ||||||||||||||
| 23 | EXT 1136 001 | France | Novel | 5 | Splicing | c.1524-2A>G | p.? | Predicted skipping of exon 9 (in-frame) or use of alternative splice site | Absent | NA | NA | NA | Caucasian | F | Dysarthria, gait disorder, akinetic–rigid syndrome, memory impairment, and dysexecutive signs | 71 | Negative | Pa, Pu, Ca, T, D, Ve, Co |
| 24 | EXT 1318 001 | France | Novel | 3 | Missense /splicing | c.1523G>A | p.(Ser508Asn) | Last base of exon 8; splicing tools predict a major effect on splicing (MaxEntScan score change:-59.5%) | Absent | DC (1) | PB (0.999) | D (0.01) | Caribbean | F | Right upper-limb dystonia, intention tremor, bradykinesia, mood disorder, and migraine | 33 | Positive for psychiatric signs | Pa |
| 25 | Proband | USA | Novel | 5 | Frameshift | c.1637_1638delCA | p.(Thr546ArgfsTer52) | Premature stop codon | Absent | NA | NA | NA | Caucasian | F | Migraine, vestibular signs | NA | Positive | Pa, Pu, Ca, and T |
| 26 | EXT 1235 001 | France | 4 | 4 | Missense | c.1753G>A | p.(Ala585Thr) | Phosphate transporter | Absent | DC (1) | PD (0.999) | T (0.09) | African | F | Dementia and parkinsonism | NA | Negative | Pa, Pu, T, Ca, D, Co |
| 27 | EXT 1138 001 | France | 4 | 5 | Frameshift | c.1755_1768del | p.(Asn587SerfsTer7) | Premature stop codon | Absent | NA | NA | NA | Caucasian | M | Mild-to- moderate intellectual disability, bipolar disorder, mild akinetic–rigid syndrome signs, ataxia, mild postural and intention tremor | 3 | Positive | Pa, Pu, Ca, T, D, T, Co |
| 28 | IT-PFBC-4 | Italy | Novel | 3 | Missense | c.1765G>A | (p.Gly589Arg) | Phosphate transporter | Absent | DC (0.99) | PD (0.99) | D (0.01) | Caucasian | F | Dementia | 81 | Positive | Pa, D |
| 29 | Proband | USA | Novel | 4 | In-frame deletion (27 bp) | c.1822_1848del | p.(Ile608_Trp616del) | Phosphate transporter | Absent | NA | NA | NA | Caucasian | M | ADHD | NA | Positive | Pa, Pu, Ca, T, Co |
| Father | M | Anxiety, dystonia | NA | Pa | ||||||||||||||
| 30 | EXT 1020 001 | France | Novel | 3 | Missense | c.1871T>A | p.(Val624Glu) | Phosphate transporter | Absent | DC (1) | PossD (0.503) | T (0.15) | Caucasian | M | Tremor of the four limbs, memory impairment with dysexecutive signs. NB: tremor, beginning from age 7, is also present in two sibpairs in the absence of brain calcification | 7 | Negative | Pa, Pu, D, WM |
ACMG class: 5—pathogenic, 4—likely pathogenic, and 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/SLC20A2 database. Reference sequences: NG_032161.1 and NM_006749.4
Associated references: [3, 4, 6, 7, 28–32]
AAO age at onset, Pa pallidum, Pu putamen, Ca caudate nuclei, T thalamus, D dentate nuclei, Co cerebral cortex, WM subcortical white matter, Ver vermis, NA not available, DC disease causing, PossD possibly damaging, PD probably damaging, T tolerated, D deleterious