Case#:Patient 52, female, 3 years old

DiseaseAssertion:Neonatal/Infantile Epileptic Encephalopathy (NIEE)

FamilyInfo:DeNovo. The family is Chinese

ParentalGenotype:The authors only conducted singleton and not trio-based exome sequencing so the parents' exomes were not sequenced.

CasePresentingHPOs:HP:0011344, HP:0002069, HP:0007359, HP:0011097, HP:0100704, HP:0001332, HP:0002072, HP:0012171.

CaseHPOFreeText:Patient 52 presents with severe global developmental delay and epilepsy.

Patient 52 has generalized tonic/clonic/tonic-clonic seizures, focal seizures and spasms. Patient 52's seizure onset occurred at 3 months old.

Patient 52 has cortical visual impairment (CVI), dystonia, chorea, and hand-washing sterotypies.

Patient History

@ 3 months - Patient 52 had generalized tonic/clonic/tonic-clonic seizures.

Patient 52 was on 3 antiepileptic drugs at most recent follow-up visit which reduced seizure frequency by >50%.

CaseNotHPOs:Not provided

CaseNotHPOFreeText:Not provided

CasePreviousTesting:The authors selected a cohort of 31 patients with seizure cryptogenic Neonatal/Infantile Epileptic Encephalopathy (NIEE) and seizure onset before 24 months.

Exclusion criteria included: (1) Patients with a definite history of brain insult, malformation of cortical development, neurocutaneous and syndromal disorders, and confirmed or highly suspected neurometabolic disorders based on clinical and biochemical markers. (2) Patients with Dravet syndrome and epilepsy at infancy with migrating focal seizure were also excluded because the majority of variants are detected in the SCN1A (>85%) and KCNT1 (approximately 50%) genes.

Formal neuropsychological testing or best clinical assessment was used to classify patient development or intelligence.

PreviouslyPublished:Not previously published

GenotypingMethod:Whole Exome Sequencing (WES) variant results were filtered in a panel of 430 epilepsy-associated genes. After selection of variants from the 430-gene panel, the synonymous variants, variants with variant frequency <10%, and variants with allele frequency >1% were removed.

Gene:CDKL5

Variant:NM_003159.2 c. 1849delC (p. Arg617Valfs*4)

The authors state that the variant is a heterozygous frameshift deletion.

The authors state that this is a novel variant and is pathogenic.

HGVS:Not provided

ClinVarID:Not found

CAID:Not found.

gnomAD:Not found

MultipleGeneVariants:Not provided

Case:Patient 2, female, 2.5 years old

DiseaseAssertion:CDKL5 Disorder

FamilyInfo:De Novo with an unremarkable family history.

ParentalGenotype:Not provided

CasePresentingHPOs:HP:0032792, HP:0007359, HP:0011154, HP:0002194, HP:0010862, HP:0000750, HP:0012434, HP:0000710, HP:0100023, HP:0000252, HP:0009062, HP:0010845, HP:0020174, HP:0010841.

CaseHPOFreeText:

Patient history

@ 2 months to 2.5 years - Patient 2 experienced tonic and focal seizures with autonomic symptoms.

@ 2 years - Patient 2 was diagnosed with CDKL5 disorder.

Patient 2 had severe delayed gross motor development, severe delayed fine motor development, severe delayed language development and delayed social development. Patient 2 had hyperoral and hand flapping stereotypies. She also had microcephaly (< 2 SD) and axial hypotonia.

Patient 2 was given a brain EEG which detected Delta slowing of the background followed by generalized attenuation during seizures and multifocal interictal epileptiform abnormalities.

@ 2.5 years - Patient 2 experienced seizures in clusters.

Treatments

Antiepleptic treatments included:Phenobarbital, Topirimate, Clobazam, Valproate, Keppra, Vitamin B6, Phenytoin, Lamotrigine, Nitrazepam, Oxcarbazepine, Mirtazipine, KCI, Levetiracetam, ant ketogenic diet.

Patient 2 was also treated with Carnitine. Patient 2's seizures seem to have changed in type over time but continued.

Other testing

Tests were conducted on Patient 2 to obtain data in the following areas: NBS, lactate, lipoprotein profile, plasma and urine amino acids, urine organic acids, acylcarnitine profile, total and free serum carnitine levels, plasma ammonia, total plasma homocysteine, serum CK, liver enzymes, urine alpha-AASA, creatine, biotinidase, VLCFA, Batten disease screen, CSF analysis (amino acids, lactate, glucose, protein, cell count, neurotransmitters), MRI-brain with spectroscopy, and karyotype.

CaseNotHPOs:Not provided

CaseNotHPOFreeText:Not provided

CasePreviousTesting:Patient 2 was given a gene sequence test for the genes SCNIA and MECP2. No gene mutation was found for these two genes.

PreviouslyPublished:Not previously published

GenotypingMethod:Patient 2 was given a CDKL5 gene sequence test. The test detected a mutation in the CDKL5 gene.

Gene:CDKL5

Variant:c. 2480_2486dupCAGATCT. frameshift

The authors state that CDKL5 gene sequencing detected a de novo duplication in exon 17, c. 2480_2486dupCAGATCT, resulting in a frameshift (Boston University School of Medicine, Center for Human Genetics, Boston, MA). This is a novel change that has not been reported before in ExAC. Only pathogenic point mutations in exon 17 have previously been reported. In a patient with a previously reported frameshift mutation in exon 18, a truncated CDKL5 transcript was detected. A truncated protein would lack the C-terminus and would not localize correctly in the cell, as demonstrated in vitro. Accordingly, any reading frame altering mutations proximal to exon 18 are null-variants. Therefore, this mutation is classified as pathogenic according to ACMG criteria.

HGVS:Not provided

ClinVarID:547188

NM_001323289.2 (CDKL5): c. 2480_2486dup (p. Gln830fs)

Allele ID: 538303

CAID:Not found

gnomAD:Not found

MultipleGeneVariants:Not provided