TABLE 4.
Genetic diagnosis, phenotype and diagnostic method in 34 cases
| Case | Gene (Ref Seq) | Mutation | Inheritance | Epilepsy syndrome | Structural or metabolic phenotype | Age, ep onset, months | Previous negative genetic investigation | Diagnostic method |
|---|---|---|---|---|---|---|---|---|
| 1 |
AP4B1 |
c.1160_1161del; p.(Thr387Argfs*30) c.1540C > T; p.(Arg514*) |
AR, compound heterozygous | ‐ | Brain malformation | 23 | FRAX, FISH Prader‐Willi, array‐CGH, Sanger MECP2 and UBE3A | WGS trio |
| 2 | ASPA (NM_000049) | c.237‐1G > A; p.? | AR, homozygous | ‐ | Canavan disease | 5 | ‐ | Sanger |
| 3 |
ATP7A |
c.1081insT; p.(Ser361fs) | XL, hemizygous (maternally inherited) | ‐ | Menkes disease | 4 | ‐ | Sanger |
| 4a | BRAT1 (NM_152743) |
c.1771‐1G > C; p.? c.294dup; p.(Leu99Thrfs*92) |
AR compound heterozygous | ‐ | Brain malformation | 1 | Chrom. analysis, subtelom. analysis, array‐CGH, Sanger CTSD and MECP2 | WGS trio |
| 4b |
BRAT1 |
c.1771‐1G > C; p.? c.294dup; p.(Leu99Thrfs*92) |
AR compound heterozygous | ‐ | Brain malformation | 1 | ‐ | WGS trio |
| 4c | BRAT1 (NM_152743) |
c.1771‐1G > C; p.? c.294dup; p.(Leu99Thrfs*92) |
AR compound heterozygous | ‐ | Brain malformation | 1 | Chrom. analysis, subtelom. analysis | WGS trio |
| 5 | FGFR3 (NM_000142) | c.1620C > A; p.(Asn540Lys) | AD, de novo | West | Hypochondroplasia | 6 | ‐ | Sanger |
| 6 |
FLVCR2 31 |
c.1289C > T; p.(Thr430Met) | AR, homozygous | West, LGS | Brain malformation | 2 | Chrom. analysis, FISH Miller‐Dieker, array‐CGH, Sanger PAFAH1B1 | WES trio |
| 7 |
FOXRED1 |
c.874G > A; p.(Gly292Arg) | AR, homozygous | ‐ | Mitochondrial disease | 2 | Chrom. analysis, mtDNA sequenc. | WGS |
| 8 |
GABRB3 |
c.380A > G; p.(Lys127Arg) | AD, de novo | MAE | ‐ | 23 | Chrom. analysis, FRAX, array‐CGH | WES trio |
| 9 |
MID2 |
c.982C > T; p.(Arg328Trp) | XL, hemizygous (maternally inherited) | ‐ | ‐ | 5 | Chrom. analysis, FISH DiGeorge, array‐CGH | WES trio |
| 10 |
MMUT (MUT) (NM_0002553) |
c.655A > T; p.(Asn219Tyr) | AR, homozygous | West | Methylmal. aciduria | 2 | ‐ | Sanger |
| 11 |
OCRL |
c.689G > A; p.(Arg230Gln) |
XL (maternally inherited) |
‐ | Brain malformation | 7 | Chrom. analysis, subtelom. analysis, array‐CGH | WES trio |
| 12 |
POLG |
c.2243G > C; p.(Trp748Ser) c.2554C > T; p.(Arg852Cys) |
AR, compound heterozygous | ‐ | Mitochondrial disease | 6 | mtDNA sequenc. | Sanger |
| 13a |
PRRT2 29 |
c.649_650insC; p.(Arg217Profs*8) | AD (paternally inherited) | BFIE | ‐ | 4 | ‐ | Sanger |
| 13b |
PRRT2 29 |
c.649_650insC; p.(Arg217Profs*8) | AD (paternally inherited) | BFIE | ‐ | 4 | ‐ | Sanger |
| 14 |
SCN1A |
c.4003‐?_4284+?del; Deletion of exon 21 |
AD, de novo | Dravet | ‐ | 6 | Sanger SCN1A | MLPA |
| 15 |
SCN2A 28 |
c.1288G > C; p.(Glu430Gln) | AD (paternally inherited) | BFIE | ‐ | 5 | ‐ | Sanger |
| 16a |
SERAC1 |
c.1228T > C; p.(Trp410Arg) | AR, homozygous | West | Mitochondrial disease | 10 | mtDNA sequenc. Sanger POLG and SMN1 | Sanger |
| 16b |
SERAC1 |
c.1228T > C; p.(Trp410Arg) | AR, homozygous | ‐ | Mitochondrial disease | 10 | ‐ | Sanger |
| 17a |
SLC12A5 30 |
c.1277T > C; p.(Leu426Pro) c.1652G > A; p.(Gly551Asp) | AR, compound heterozygous | EIMFS | ‐ | 3 | Chrom. analysis, FISH Angelman, array‐CGH, Sanger UBE3A and SCN1A | WES trio |
| 17b |
SLC12A5 30 |
c.1277T > C; p.(Leu426Pro) c.1652G > A; p.(Gly551Asp) | AR, compound heterozygous | EIMFS | ‐ | 3 | ‐ | WES trio |
| 18 |
STXBP1 |
c.326‐2A > G; p.? | AD, de novo | ‐ | ‐ | 21 | Chrom. analysis, array‐CGH | WGS trio |
| 19 |
STXBP1 |
c.614_615del; p.(Ile205fs) | AD, de novo | West | ‐ | 1 | Chrom. analysis, FRAX, subtelomeric analys | WES trio |
| 20 |
TSC2 |
c.3779C > A; p.(Ser1254*) | AD, de novo | West | Tuberous sclerosis | 6 | ‐ | Sanger |
| 21 |
TSC2 |
c.1137 + 1G>C; p.? | AD, de novo | West | Tuberous sclerosis | 1 | ‐ | Sanger |
| 22 |
WDR45 |
c.38G > C; p.(Arg13Pro) | XL (de novo) | ‐ | ‐ | 18 | array‐CGH, mtDNA sequencing | WGS trio |
| 23 | ZEB2 (NM_014795) |
c.808‐2A > G; p.? |
AD, de novo | ‐ | Mowat‐Wilson syndrome and brain malformation | 16 | Chrom. analysis, array‐CGH, sequenc. POMGNT1, PPT1, CLN3 and CLN5 | WGS trio |
| Chromosomal abnormality | ||||||||
| 24,25,26,27 | Trisomy 21 | West in all 4 cases | Down syndrome | 3,5,5,6 | ‐ | Chromos. analysis | ||
| 28 | Del22q11.2 | ‐ | DiGeorge syndrome | 5 | ‐ | FISH | ||
| 29 | Partial tetrasomy 14q | ‐ | ‐ | 2 | ‐ | Array‐CGH | ||
AD, autosomal dominant; AR, autosomal recessive; BFIE, benign familial infantile epilepsy; EIFMS, epilepsy in infancy with migrating focal seizures; LGS, Lennox‐Gastaut syndrome; MAE, myoclonic atonic epilepsy; MLPA, multiplex ligation‐dependent probe amplification; Sanger, Sanger sequencing of the target gene only; Trio, proband + parents; WES, whole exome sequencing; WGS, whole genome sequencing; XLR, X‐linked recessive