Table 2.
Mutations and affected genes identified for each subject
| Subject | Gene | Variant | ACMG variant classificationa | Genomic location | Novel gene/known EIEE gene/previously reported |
|---|---|---|---|---|---|
| 1 | KCNQ2 | c.841G>A, p.G281R | Pathogenic (PS1, PS2, PM2, PP3, PP5) | chr20:62071037 | Known gene, previously reported mutation43,55 |
| 2 | Multiple | Balanced inverted translocation between Chr2 and ChrX | chrX:151118513 chr2:59405748 |
Novel structural mutation similar to previously structural rearrangement42 | |
| 3 | SCN8A | c.1219T>G, p.L407V | Pathogenic (PS2, PM2, PM5, PP2, PP3) | chr12:52099285 | Known gene, previously reported mutation at this site56 |
| 4 | PIGA | c.502A>C, p.N168H | Likely pathogenic (PS2, PM2, PP3) | chrX:15349551 | Known gene, novel mutation |
| 5 | SCN8A | c.800T>C, p.L267S | Likely pathogenic (PS2, PM2, PP2, PP3, PP5) | chr12:52093447 | Known gene, novel mutation (same patient and mutation reported concurrently in Malcolmson et al.57) |
| 6 | EEF1A2 | c.1267C>T, p.R423C | Pathogenic (PS1, PS2, PM2, PP3) | chr20:62119776 | Known gene, previously reported mutation58 |
| 7 | CDKL5 | c.146-14735_2276+3273dup | Pathogenic (PVS1, PS2, PM2, PP3, PP5) | chrX:18567862 -18630963 | Known gene with previously reported loss of function mutations28–30 |
| 8 | SCN2A | c.647T>G, p.L216W | Likely pathogenic (PS2, PM2, PP2, PP3) | chr2:166165903 | Known gene, novel mutation |
| 9 | DEAF1 | c.634G>A, p.G212S | Pathogenic (PS1, PS2, PS3, PM2, PP3, PP2) | chr11:687941 | Known gene, previously reported mutation33 |
| 10 | CAMK2G | c.719C>T, p.T240M | Likely pathogenic (PS2, PM2, PP2, PP3) | chr10:75607083 | Novel gene |
| 11 | STXBP1 | c.1151dup, p.D385Gfs*19 | Pathogenic (PVS1, PS2, PM2, PP3) | chr9:130438123 | Known gene, previously reported loss of function mutations33,43 |
| 12 | SCN8A | c.2642T>C, p.V881A | Likely pathogenic (PS2, PM2, PP2, PP3, PP5) | chr12:52159552 | Known gene, novel mutation |
| 13 | SCN1A | c.4736T>C, p.L1590P | Likely pathogenic (PS2, PM2, PP2, PP3) | chr2:166850739 | Known gene, novel mutation |
| 14 | KCNQ2 | c.833T>C, p.I278T | Likely pathogenic (PS2, PM1, PM2, PP3) | chr20:62071045 | Known gene, novel mutation |
aPVS1—Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease
PS1—Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
PS2—De novo (both maternity and paternity confirmed) in a patient with the disease and no family history
PS3—Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
PS4—Prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
PM1—Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
PM2—Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
PM5—Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
PP2—Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
PP3—Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
PP5—Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation