CaseGuC: Male, 5 days onset

CasePresentingHPOs: HP:0200134, HP:0011153, HP:0010850, HP:0011199, HP:0001252, HP:0003487, HP:0003423, HP:0010864, HP:0011344, HP:0002188, HP:0002059 (Epileptic encephalopathy, Focal motor seizure, EEG with spike-wave complexes, EEG with generalized sharp slow waves, Muscular hypotonia, Babinski sign, Thoracolumbar kyphoscoliosis, Severe intellectual disability, Severe global developmental delay, Delayed CNS myelination, Cerebral atrophy)

HPOsFreeText: Multiple seizure types, Bilateral T2 prolongation in caudate heads and putamina

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed heterozygous de novo

CasePreviousTesting: Investigations include electroencephalography (EEG), head MRI, neurometabolic testing, and chromosome microarray; Individuals with self-limiting benign electroclinical syndromes, such as childhood absence epilepsy (onset > 4 years), were excluded; Head circumference was 44 cm at 4 months (91st percentile); Partial response to ketogenic diet and phenytoin, no response to other antiseizure medications;

CaseGenotypingMethod: Variants within co-expressed candidate genes in Table S1 were extracted from exome sequencing data. Variants were annotated and were verified with Sanger sequencing of the proband and parents.

Variant: NM_004171.4(SLC1A2):c.866C>G (p.Pro289Arg)

ClinVar: 438737, https://www.ncbi.nlm.nih.gov/clinvar/variation/438737/

gnomAD: Not in gnomAD

CaseGuA: Male, 6 weeks onset

CasePresentingHPOs: HP:0200134, HP:0020217, HP:0002069, HP:0010852, HP:0012012, HP:0012017, HP:0012018, HP:0010841, HP:0025152, HP:0030211, HP:0008936, HP:0002061, HP:0006986, HP:0002187, HP:0011344, HP:0001344, HP:0012448, HP:0002283, HP:0002079, HP:0012696, HP:0002500, HP:0012751 (Epileptic encephalopathy, Focal aware motor seizure, Bilateral tonic-clonic seizure, EEG with parietal focal spike waves, EEG with parietal focal spikes, EEG with temporal focal spikes, Multifocal epileptiform discharges, Poor visual behavior for age, Slow pupillary light response, Muscular hypotonia of the trunk, Lower limb spasticity, Upper limb spasticity, Profound intellectual disability, Severe global developmental delay, Absent speech, Delayed myelination, Global brain atrophy, Thin corpus callosum, Abnormal thalamic MRI signal intensity, White matter abnormalities, Abnormal basal ganglia MRI signal intensity)

HPOsFreeText: Dyskinetic movements of arms, In ability to sit unsupported, Abnormal MRI signal in putamen and caudate

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed heterozygous de novo

CasePreviousTesting: Investigations include electroencephalography (EEG), head MRI, neurometabolic testing, and chromosome microarray; Individuals with self-limiting benign electroclinical syndromes, such as childhood absence epilepsy (onset > 4 years), were excluded; Capture of right arm jerks and chin twitching showed no EEG correlate; Head circumference was 45.1 cm at 8 months (50%), 52 cm at 5 years (50th percentile); Partial response to phenobarbital, levetiracetam, and clobazam; Longest seizure-free period was 16 months

CaseGenotypingMethod: Variants within co-expressed candidate genes in Table S1 were extracted from exome sequencing data. Variants were annotated and were verified with Sanger sequencing of the proband and parents.

Variant: NM_004171.4(SLC1A2):c.244G>A (p.Gly82Arg)

ClinVar: 438736, https://www.ncbi.nlm.nih.gov/clinvar/variation/438736/

gnomAD: Not in gnomAD

CaseWA: Male, 2 yrs onset, Germany

CasePresentingHPOs: HP:0002013, HP:0012470, HP:0004372, HP:0002069, HP:0010819, HP:0007359, HP:0010845, HP:0002133, HP:0007979, HP:0000572, HP:0000577, HP:0000543, HP:0001263, HP:0001310, HP:0002075, HP:0002317, HP:0002188 (Vomiting, Setting-sun eye phenomenon, Lowered consciousness, Bilateral tonic-clonic seizure, Atonic seizure, Focal-onset seizure, EEG with generalised slow activity, Status epilepticus, Gaze-evoked horizontal nystagmus, Visual loss, Exotropia, Optic disc pallor, Global developmental delay, Dysmetria, Dysdiadochokinesis, Unsteady gait, Delayed CNS myelination)

HPOsFreeText: Tonic flexion of the right limbs, The right hemisphere showed continuous spike and slow-spike waves with a temporo-occipital maximum

CaseNotHPOs: HP:0010841 (Multifocal epileptiform discharges)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are nonconsanguineous, Proband is confirmed homozygous via parental testing

CasePreviousTesting: EEG showed severe cerebral dysfunction of the right hemisphere (continuous subdelta and delta activity); Antiepileptic treatment with phenobarbital was initiated after the first seizure but was replaced by levetiracetam after the second seizure

CaseGenotypingMethod: Exome sequencing was performed and potential variants prioritized. Identified variants were selected for Sanger sequencing in both the proband and parents.

Variant: NM_004171.4:c.1421+1G>C

CAID: CA380121375, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA380121375

gnomAD: Not in gnomAD

CaseEG1291: Female, 5 days onset

CasePresentingHPOs: HP:0200134, HP:0012469, HP:0032794, HP:0032667, HP:0002187, HP:0032792, HP:0002069, HP:0007359, HP:0010841, HP:0002188, HP:0006913, HP:0002079, HP:0001290 (Epileptic encephalopathy, Infantile spasms, Myoclonic seizure, Myoclonic status epilepticus, Profound intellectual disability, Tonic seizure, Bilateral tonic-clonic seizure, Focal-onset seizure, Multifocal epileptiform discharges, Delayed CNS myelination, Frontal cortical atrophy, Hypoplasia of the corpus callosum, Generalized hypotonia)

HPOsFreeText: N/A

CaseNotHPOs: HP:0002521 (Hypsarrhythmia)

NotHPOsFreeText: N/A

CaseAddInfo: Proband confirmed de novo heterozygous by parental sequencing; Father had two seizures as an adult, no further seizures while on LTG

CasePreviousTesting: Currently on levitiracetam and valproate; previously on pyridoxine, prednisolone, vigabatrin, zonisamide and ketogenic diet

CaseGenotypingMethod: About 10% of the original 290 genes where a single de novo variant had been identified was chosen for targeted sequencing in a new cohort. Most of these individuals had been tested for mutations of known and novel candidate genes as well as pathogenic copy-number variants. These genes were sequenced in the parents and proband to look for de novo variants.

Variant: NM_004171.4(SLC1A2):c.244G>C (p.Gly82Arg)

ClinVar: 254265, https://www.ncbi.nlm.nih.gov/clinvar/variation/254265/

gnomAD: Not in gnomAD

CaseT23159: Female, 2 days onset

CasePresentingHPOs: HP:0200134, HP:0011167, HP:0010818, HP:0032667, HP:0031475, HP:0032816, HP:0010841, HP:0010845, HP:0006808, HP:0002079, HP:0012753, HP:0002059, HP:0007266, HP:0002273, HP:0011471, HP:0000121, HP:0000141, HP:0000696, HP:0001662, HP:0002045, HP:0000253, HP:0000341, HP:0001525, HP:0001007, HP:0002751, HP:0001371, HP:0001182 (Epileptic encephalopathy, Focal tonic seizure, Generalized tonic seizure, Myoclonic status epilepticus, Nonconvulsive status epilepticus, Neonatal multifocal myoclonic seizure, Multifocal epileptiform discharges, EEG with generalized slow activity, Cerebral hypomyelination, Hypoplasia of the corpus callosum, T2 hypointense basal ganglia, Cerebral atrophy, White matter dysmyelination/demyelination, Tetraparesis, Gastrostomy tube feeding in infancy, Nephrocalcinosis, Amenorrhea, Delayed eruption of permanent teeth, Bradycardia, Hypothermia, Progressive microcephaly, Narrow forehead, Severe failure to thrive, Hirsutism, Kyphoscoliosis, Flexion contracture, Tapered finger)

HPOsFreeText: Thinning of cortical gray matter

CaseNotHPOs: HP:0001272 (Cerebellar atrophy)

NotHPOsFreeText: Hypomyelination of cerebellum and brain stem

CaseAddInfo: Proband confirmed de novo heterozygous by parental sequencing

CasePreviousTesting: Currently on carbamazepime, lamotrigine and lacosamide; previously on pyridoxine, clonazepam, acetazolamide, valproate, phenobarbitone, phenytoin, prednisolone, vigabatrin, topiramate and ketogenic diet

CaseGenotypingMethod: About 10% of the original 290 genes where a single de novo variant had been identified was chosen for targeted sequencing in a new cohort. Most of these individuals had been tested for mutations of known and novel candidate genes as well as pathogenic copy-number variants. These genes were sequenced in the parents and proband to look for de novo variants.

Variant: NM_004171.4(SLC1A2):c.254T>C (p.Leu85Pro)

ClinVar: 254266, https://www.ncbi.nlm.nih.gov/clinvar/variation/254266/

gnomAD: Not in gnomAD

CaseEPI4Kn2: Female, 1 month onset

CasePresentingHPOs: HP:0002521, HP:0011167, HP:0032794, HP:0000618, HP:0003089, HP:0000473, HP:0003487, HP:0032988, HP:0008936, HP:0001276, HP:0010864 (Hypsarrhythmia, Focal tonic seizure, Myoclonic seizure, Blindness, Hamstring contractures, Torticollis, Babinski sign, Persistent head lag, Muscular hypotonia of the trunk, Hypertonia, Severe intellectual disability)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001263 (Global developmental delay)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Currently on vigabatrin, topiramate, and oxcarbazepine; Previously on phenobarbitone and levetriacetam; Bifrontal central frequent discharges on EEG; Normal brain imaging; No confirmed genetic or metabolic diagnosis, and no history of congenital TORCH infection, premature birth (before 32 weeks gestation), neonatal hypoxic-ischemic encephalopathy or neonatal seizures, meningitis/encephalitis, stroke, intra-cranial hemorrhage, significant head trauma, or evidence of acquired epilepsy

CaseGenotypingMethod: Exome sequencing was performed from primary DNA in parental leukocytes. Coding regions of the genome were sequenced in a trio in order to determine which loci bearing de novo mutations were present according to specifications. All candidate de novo variants were confirmed with Sanger sequencing of the proband and parents.

Variant: NM_004171.4(SLC1A2):c.244G>C (p.Gly82Arg)

ClinVar: 254265, https://www.ncbi.nlm.nih.gov/clinvar/variation/254265/

gnomAD: Not in gnomAD

CaseST: Female, 2 days onset

CasePresentingHPOs: HP:0002521, HP:0010841, HP:0012000, HP:0032842, HP:0011468, HP:0007289, HP:0100704, HP:0000639, HP:0001601, HP:0012820, HP:0002835, HP:0001252, HP:0001257, HP:0001263, HP:0002079, HP:0011757, HP:0003429 (Hypsarrhythmia, Multifocal epileptiform discharges, EEG with generalized spikes, Generalized-onset epileptic spasm, Facial tics, Limb fasciculations, Cerebral visual impairment, Nystagmus, Laryngomalacia, Bilateral vocal cord paralysis, Aspiration, Muscular hypotonia, Spasticity, Global developmental delay, Hypoplasia of the corpus callosum, Posterior pituitary hypoplasia, CNS hypomyelination)

HPOsFreeText: Lack of normal sleep or wake features on EEG

CaseNotHPOs: HP:0002650 (Scoliosis)

NotHPOsFreeText: N/A

CaseAddInfo: Proband is confirmed de novo heterozygous

CasePreviousTesting: Currently on vigabatrin, levetiracetam, Rufinamide and ketogenic diet, previously on phenobarbatol, ACTH, Cannabidiol oil and Prednisolone; MRS with small lactate peaks in the basal ganglia and supratentorial white matter

CaseGenotypingMethod: Whole exome sequencing revealed a pathogenic heterozygous c.254T>C (p.Leu85Pro) variant in the SLC1A2 gene, which was classified as de novo using parental testing.

Variant: NM_004171.4(SLC1A2):c.254T>C (p.Leu85Pro)

ClinVar: 254266, https://www.ncbi.nlm.nih.gov/clinvar/variation/254266/

gnomAD: Not in gnomAD