Table 2. Nonrecurrent Rare Pathogenic or Likely Pathogenic CNVs and Candidate Gene Information for Epilepsy With ID.
| CNV | Similar Deletions or Duplications Previously Described and Associated Clinical Features | Genes in Region | Known or Candidate Epilepsy Gene(s) | Associated Disease(s) and Mode of Inheritance | RVIS (% of MIG) | Gene Expression Studies | Added Information From This Case |
|---|---|---|---|---|---|---|---|
| 2p16.1-p15 duplicate (1.70 Mb) | 2p15-16.1 deletion syndrome (OMIM 612513) and 2p16.1 deletion: delayed psychomotor development, ID, microcephaly, brain malformations, autistic features, attention deficit, and dysmorphic features | PEX13, MIR4432, BCL11A, PAPOLG, FLJ16341, REL, PUS10, KIAA1841, LOC339803, C2orf74, AHSA2, USP34, SNORA70B, and XPO1 | BCL11A | Chromosome 2p16.1-p15 deletion syndrome (OMIM 612513) (ICs), intellectual developmental disorder with persistence of fetal hemoglobin (OMIM 617101) (AD) | –1.16 (6.1) | Expressed in neural tissues | 2p16.1-p15 duplications were not previously reported in association with seizures; BCL11A is required for neuronal cell polarity switch and migration of the upper layer projection neurons |
| 6p25.3-p25.1 duplicate (6.58 Mb) | 6p25 duplication: developmental ocular abnormalities, ID, craniofacial anomalies, and renal complications | 45 RefSeq genes, including IRF4, FOXC1, SERPINB6, TUBB2A, FARS2, and F13A1 | TUBB2A | Complex cortical dysplasia with other brain malformations) (OMIM 615763) (AD) | –0.12 (44.5) | High expression in neural tissues | 6p25.3-25.1 duplication has not been associated with seizures; TUBB2A heterozygous mutations have been associated with complex structural brain malformations not seen in our patients 4 and 5; these patients also have a 9p24.3-p23 deletion |
| 8p23.3p23.1 deletion (11.0 Mb) | 8p23 deletions: mild dysmorphic features, developmental delay | 92 RefSeq genes, including CLN8, ARHGEF10, MCPH1, and RP1L1 | MCPH1, CLN8 | Microcephaly, primary (OMIM 607117) (AR); ceroid lipofuscinosis, neuronal (OMIM 600143) (AR) | 1.39 (94.6), –0.14 (43.7) | Expressed in fetal brain, particularly forebrain and walls of lateral ventricles; expressed throughout development and in mature brain | Although seizures may be present in patients with MCPH1 and CLN8 mutations, these genes are associated with AR disorders; at present, it is not possible to determine how this CNV contributes to patient 9’s seizure phenotype |
| 9p24.3-p23 deletion (12.0 Mb) | Overlaps with described distal 9p deletions: ID, dysmorphic features | 47 RefSeq genes, including DOCK8, KANK1, SMARCA2, VLDLR, KCNV2, GLIS3, SLC1A1, JAK2, and GLDC | KANK1, SMARCA2 | Cerebral palsy, spastic quadriplegic (OMIM 612900); inheritance pattern to be determined, Nicolaides-Baraitser syndrome (OMIM 601358) (AD) | –0.92 (9.78), –1.97 (1.82) | Expression in most tissues, including neural tissue; high expression in the cerebral cortex | KANK1 deletion was described in 9 children with congenital neurodegenerative disease evolving to spastic quadriplegia, transient nystagmus, and ID; Nicolaides-Baraitser syndrome, caused by heterozygous mutations of SMARCA2, is characterized by severe ID, dysmorphic features, sparse hair, behavioral problems, and seizures; patients 4 and 5 presented with behavioral problems and adolescence onset of seizures but no myoclonic-astatic seizures or dysmorphisms, resembling Nicolaides Baraitser syndrome |
| 10q11.22-q11.23 duplicate (1.73 Mb) | Rare 10q11.22-q11.23 duplications described: phenotypic features not described | 22 RefSeq genes, including GPRIN2, ERCC6, and CHAT | GPRIN2 | Likely modifier of Rett syndrome, likely corroborant of autism and ID, and inheritance pattern to be determined | 1.09 (91.9) | Medium expression in neural tissues, highly expressed in the cerebellum | Genes within this interval have not been previously associated with seizures |
| 12p13.33-13.2 duplicate (11.0 Mb) | Nil of this size | 190 RefSeq genes, including WNK1, CACNA2D4, CACNA1C, FGF23, KCNA1, KCNA5, VWF, TNFRSF1A, SCNN1A, CD4, GNB3,TPI1, ATN1, EMG1, C1S, PEX5, GDF3, AICDA, A2M, CLEC7A, and OLR1 | KCNA1,CACNA1C | Episodic ataxia, myokymia, and seizures (OMIM 176260) (AD); Timothy syndrome, affects multiple systems, and includes autism and ID (OMIM 601005) (AD) | –0.56 (19.5), –2.09 (1.5) | Predominantly neural tissues, ubiquitous expression | Patient 12 presented with an unbalanced translocation, resulting in a partial trisomy of chromosome region 12p13.2 to 12p ter and partial monosomy of region 13q34 to 13q ter; at present, it is not possible to determine the effects of KCNA1 and CACNA1C duplications in patient 12; seizures have been reported in only 1 patient with a 12p13.33 duplication and 15q11.2 deletion or uncertain inheritance, overlapping the CACNA1C gene |
| 13q34 deletion (4.39 Mb) | 4 Patients with 13q33-34 deletions, all presenting microcephaly and ID | 39 RefSeq genes, including COL4A1, ING1, F7, F10, and GRK1 | COL4A1 | Porencephaly-1 (OMIM 175780) (AD), HANAC syndrome (OMIM 611773) (AD), brain small vessel disease with or without ocular anomalies (OMIM 607595) (AD), and susceptibility to intracerebral hemorrhage (OMIM 614519) (AD) | –2.82 (0.6) | Low expression in neural tissues | COL4A1 mutations are usually associated with brain structural abnormalities not found in patient 12 |
| 16p13.2 duplicate (0.08 Mb) | None encompassing the same gene content | ABAT, METTL22 | ABAT | GABA-transaminase deficiency (OMIM 613163) (AR) | –0.33 (30.7) | High expression in neural tissues | Homozygous or compound heterozygous ABAT mutations underlie a severe neurologic condition characterized by psychomotor retardation and refractory seizures attributable to GABA-transaminase deficiency; because our patient presents with duplication, we hypothesize whether he has an overexpression of ABAT leading to a hypo-GABAergic state |
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CNV, copy number variation; GABA, γ-aminobutyric acid; HANAC, hereditary angiopathy with nephropathy, aneurysms, and muscle cramps; ICs, isolated cases; ID, intellectual disability; MIG, most intolerant genes; RefSeq, reference sequence; RVIS, Residual Variation Intolerance Score.