Case: Patient 1, female, 2 years old

DiseaseAssertion: Rett Syndrome

FamilyInfo: DeNovo. Patient 1 was the second child of a nonconsanguineous Chinese couple. Patient 1 was born at full term with a birth weight of 3.83 kg.

ParentalGenotype(s):Not provided

CasePresentingHPOs:HP:0011344, HP:0001250, HP:0001252, HP:0000252, HP:0000748, HP:0003763, HP:0005469, HP:0000486, HP:0012171.

CaseHPOFreeRext:Patient 1 presents with severe global developmental delay, epilepsy, and hypotonia. The Patient History contains all of Patient 1's phenotypes along with the progression of her condition.

Patient History

@ 3 months - Patient 1 had microcephaly (head circumference was less than 3rd percentile with a body weight and body height at 75th percentile). Patient 1 had hypotonia.

Patient 1 was given a metabolic screening, a muscle enzyme, and a brain tomography with normal results.

@ 6 months - Patient 1 had microcephaly, flat occiput, right divergent squint, and hypotonia. No syndromal diagnosis could be ascertained at that time.

@ 2 years - Patient 1 had epilepsy.

Patient 1 had severe global development delay.

Patient 1 was given an EEG which showed nonspecific background slowing, but no epileptiform abnormalities. Patient 1 was also given a brain MRI which showed mild thinning of corpus callosum without major structural defect. Patient 1 had no developmental regression but she developed stereotypical hand movements, bruxism, and occasional outburst of laughter.

Based on these phenotypes, Angelman/Rett Syndrome was suspected.

CaseNOTHPOs: HP:0002353.

CaseNOTHPOFreeText: Patient 1 was given an EEG which detected no epileptic abnormalites.

CasePreviousTesting: Genetic investigations (including methylation-specific multiplex ligation-dependent probe amplification (MS-MLLPA)) was conducted for Angelman Syndrome, UBE3A gene, MECP gene, and array CGH. These studies were negative. A FOXG1 related disease was suspected

PreviouslyPublished:Not previously published

GenotypingMethod: A FOXG1 gene test showed a de novo frameshift pathogenic mutation FOXG1 {NM_005249.3} c. 396_397ins26; FOXG1{NP_005240.3} :(p. Gly133TRPfs*68) which confirmed the diagnosis of a FOXG1 related congenital variant of Rett Syndrome.

Gene:FOXG1

Variant: (NM_005249.3) c. 396_397ins26 (p. Gly133Trpfs*68)

HGVS:Not provided

ClinVarID:Not found

CAID:Not found

gnomAD:Not found

Case:Patient 2, female, Chinese

DiseaseAssertion:Global delay

FamilyInfo:Patient 2 was the first child of nonconsanguineous Chinese couple born at 38-week gestation. The mother had gestational diabetes mellitus that required insulin therapy.

ParentalGenotype:Not provided

CasePresentingHPOs:HP:0000365, HP:0020049, HP:0000252, HP:0001263, HP:0012171, HP:0000154, HP:0000708, HP:0003763, HP:0002376, HP:0012433.

CaseHPOFreeText:

Patient History

@ birth - Patient 2 presented with mild grade bilateral hearing impairment and left divergent squint diagnosed at birth.

@ Follow-up visit - Patient 2 had microbrachycephaly and global developmental delay. Brain MRI, metabolic screening and array CGH were normal.

@ 1 year - Patient 2 had stereotypical handwashing movement.

There was no clinical or electrical seizure.

Patient 2 has craniofacial features like microbrachycephaly, wide mouth, divergent squint, and behavioral phenotype.

@ 1.5 years - Patient 2 had bruxism and developmental regression. Patient 2 also had loss of some motor and social skills.

CaseNotHPOs:HP:0001250

CaseNotHPOFreeText:Patient 2 has no seizures.

CasePreviousTesting:Not provided

PreviouslyPublished:Not previously published

GenotypingMethod:Not provided

Gene:MECP2 (MN_004992.3) (NP_004983.1)

Variant:c. 808C>T (p. Arg270*)

HGVS:Not provided

ClinVarID:Not found

CAID:CA172577

gnomAD:Not found

MultipleGeneVariants:NA

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