Table 2.
High and moderate confidence variants identified in established PME genes
| Patient ID country of origin | Sex | Gene (GenBank) | Variant(s) (LOVD ID) | gnomAD MAF | Inheritance | Clinical summary (onset age) | WES study design | Confidence |
|---|---|---|---|---|---|---|---|---|
| PME83 Australia | M | SEMA6B (NM_032108.4) | c.1993delC (p.Arg665Glyfs∗20) (het) (#00334899) | 0 | AD | developmental delay and regression; ataxia, tremor (2.5y); drop attacks and absence seizures (4y), TCS (11y), wheelchair (11y), multifocal myoclonus (15 y); severe ID | singletona | high |
| PME25 Canada | F | SEMA6B (NM_032108.4) | c.2032delG (p.Glu678Argfs∗7) (het) (#00334902) | 0 | AD | developmental delay; ataxia (2.5y); TCS (5y), resting and action myoclonus (10y), possible absence and focal seizures, tremor, wheelchair (14y); moderate ID | singleton | moderate |
| PME15 Italy | F | CLN6 (NM_017882.3) | c.486+28T>C (splicing) (hom)b (#00334904) | 0 | AR | ataxia (14y); severe myoclonus (32y), TCS, dementia, pyramidal signs, psychiatric co-morbidities | singleton | high |
| PME26 (dec.) Germany | M | GBA (NM_001005742.2) | c.761+4A>G (splicing) (hom) (#00334906) | 0 | AR | myoclonus (8y); ataxia, ophthalmoplegia, mild cognitive impairment, splenomegaly | singleton | moderate |
| PME10 Malaysia | M | NEU1 (NM_000434.3) | c.544A>G (p.Ser182Gly); deletion of NEU1 (comp het) (#00334907) | 0.001; 0 | AR | occasional TCS (12y); frequent myoclonus (14y), ataxia, normal cognition, visual deterioration (20y), cherry-red spots (21y) | trio | high |
| PME7 Israel | F | CERS1 (NM_021267.4) | c.210G>A (p.Trp70∗); c.202C>A (p.Leu68Met) (both hom) (#00334908), (#00334910) | 0; 0 | AR | action myoclonus (11/16yr); ataxia, occasional TCS, mild cognitive impairment | sibling pair; quartet | high |
| PME8 Israel | F | |||||||
| PME9 (dec.) Australia | M | ASAH1 (NM_004315.4) | c.966−2A>G, splicing; c.504A>C (p.Lys168Asn) (comp het) (#00334911) | 0.000004; 0.00006 | AR | multifocal myoclonus (10y). TCS, progressive limb and bulbar weakness (16y); hearing impairment (4y); deceased (19y) | trio | high |
Abbreviations: MAF, minor allele frequency; comp het, compound heterozygous; hom, homozygous; AR, autosomal recessive; gnomAD, The Genome Aggregation Database; dec., deceased; TCS, tonic-clonic seizure. Detailed clinical summaries can be found in Table S5. See subjects and methods for criteria followed when classifying variants as high versus moderate confidence.
a
Variant subsequently confirmed de novo by Sanger sequencing; maternal DNA did not meet quality control requirements for WES.
b
Splicing effect of intronic variant confirmed by RT-PCR (see Figure S4).