Table 3.
High and moderate confidence variants identified in established disease genes (not PME)
| Patient ID country of origin | Sex | Gene (GenBank) | Disease previously associated with gene (MIM ID) | Variant(s) (LOVD ID) | gnomAD MAF | Inheritance | Clinical presentation | WES study design | Confidence |
|---|---|---|---|---|---|---|---|---|---|
| PME11 Italy | M | CHD2 (NM_001271.3) | epileptic encephalopathy, childhood-onset (MIM: 615369) | c.532A>T (p.Arg178∗) (het) (#00334913) | 0 | de novo | frequent absence seizures and rare TCS (6y), severe myoclonus (14y); ataxia, dementia; developmental delay | trio | high |
| PME19 Italy | M | CACNA2D2 (NM_001174051.2) | cerebellar atrophy with seizures and variable developmental delay (MIM: 618501) | c.1260G>A (p.Thr420=) (het, de novo); c.1112A>G (p.Tyr371Cys) (het, pat inherited) (#00334914) | 0; 0 | AR | myoclonus, absence and tonic seizures (4y); dementia, no ataxia; developmental delay | trio | high |
| PME4 (dec.) Italy | F | STUB1 (NM_005861.4) | autosomal-recessive spinocerebellar ataxia 16 (MIM: 615768); spinocerebellar ataxia 48 (MIM: 618093) | c.169C>T (p.Pro57Ser) (hom) (#00334915) | 0 | AR | ataxia (12y); myoclonus, TCS (30y); dementia; tetraparesis | trio | high |
| PME16 Italy | F | CACNA1A (NM_001127222.2) | early infantile epileptic encephalopathy (MIM: 617106); spinocerebellar ataxia 6 (MIM: 183086); episodic ataxia type 2 (MIM: 108500); familial heiplegic migraine 1 (MIM: 141500); familial hemiplegic migraine 1 with progressive cerebellar ataxia (MIM: 141500) | c.4897G>A (p.Asp1633Asn) (het)a (#00334917) | 0 | unknown | ataxia, myoclonus (30y); cognitive impairment; sensorineural hearing impairment | singleton | moderate |
| PME17 Italy | F | CAMTA1 (NM_015215.4) | non-progressive cerebellar ataxia with mental retardation (MIM: 614756) | c.4418G>C (p.Ser1473Thr) (het) (#00334922), (#00334925) | 0.000004 | AD | myoclonus (18y), no TCS; no ataxia or dementia | parent-child | moderate |
| PME18 Italy | M | myoclonus, rare TCS (25y); no ataxia or dementia | |||||||
| PME21 Malta | M | PEX19 (NM_001193644.1) | peroxisome biogenesis disorder 12A (Zellweger) (MIM: 614886) | c.254C>T (p.Ala85Val) (hom) (#00334927), (#00334928) | 0.0009 | AR | progressive ataxia (7yr); myoclonus, TCS (9y), dementia (10y); limb spasticity | sibling pair | high |
| PME22 Malta | M | progressive ataxia (8y); myoclonus, TCS (9y); dementia (10y); limb spasticity | |||||||
| PME60 (dec.) Malta | F | PEX19 (NM_001193644.1) | Peroxisome biogenesis disorder 12A (Zellweger) (MIM: 614886) | c.254C>T (p.Ala85Val) (hom) (#00334930) | 0.0009 | AR | progressive severe ataxia (8y); TCS (12y); hypertonia | singleton | high |
| PME5 (dec.) Italy | F | NAXE (NM_144772.2) | encephalopathy, progressive early-onset, with brain edema and/or leukoencephalopathy (MIM: 617186) | c.128C>A (p.Ser43∗) (hom) (#00334932) | 0.00003 | AR | versive motor seizures (12y), daily absence (13y) and myoclonus (15y), rare TCS (21y); slowly progressive ataxia (19y) dementia and pyramidal signs; developmental delay | singleton | high |
| PME12 Italy | M | RARS2 (NM_020320.3) | pontocerebellar hypolasia type 6 (MIM: 611523) | c.943C>T (p.Arg315∗); c.425T>C (p.Val142Ala) (comp het) (#00334933), (#00334935) | 0.00004; 0.00005 | AR | mild ataxia (childhood), moderate cognitive impairment; rare TCS and absence seizures (9y), mild myoclonus (11y) | sibling pair; quartet | moderate |
| PME13 Italy | F | ataxia (childhood), moderate cognitive impairment; rare TCS and absence seizures (9), myoclonus (11y) | |||||||
| PME14 Italy | F | RARS2 (NM_020320.3) | pontocerebellar hypolasia type 6 (MIM: 611523) | c.1026G>A (p.Met342Ile); c.3G>A (p.Met1Ile) (comp het) (#00334936) | 0.0002; 0 | AR | prominent progressive action myoclonus (25y); no TCS, no ataxia, no dementia | trio | moderate |
| PME64 Italy | M | DYNC1H1 (NM_001376.4) | Charcot-Marie-Tooth disease axonal type 20 (MIM: 614228); mental retardation, autosomal-dominant 13 (MIM: 614563); spinal muscular atrophy lower extremity-predominant (MIM: 158600) | c.7828delC (p.Arg2610Glyfs∗23) (het) (#00334938) | 0 | de novo | myoclonus (12y), refractory TCS and absence seizures (22y); no ataxia or dementia | trio | moderate |
Abbreviations: MAF, minor allele frequency; AR, autosomal recessive; comp het, compound heterozygous; het, heterozygous; hom, homozygous; AD, autosomal dominant; gnomAD, The Genome Aggregation Database; dec., deceased; TCS, tonic-clonic seizure. Detailed clinical summaries can be found in Table S5. Please see subjects and methods for criteria followed when classifying variants as high versus moderate confidence.
a
See Figure S7 for molecular modeling that supports a loss-of-function effect for this CACNA1A variant.