Case#:Patient 7, male, 5 years old

DiseaseAssertion:Neonatal/Infantile Epileptic Encephalopathy (NIEE)

FamilyInfo:The family is French/Chinese

ParentalGenotype:The variant was inherited from Patient 7's asymptomatic mother.

CasePresentingHPOs:HP:0010864, HP:0012758, HP:0000729, HP:0007359, HP:0002069, HP:0032794, HP:0001250, HP:0000252.

CaseHPOFreeText:Patient 7 presents with severe intellectual disability, developmental slowdown, and various seizure types. Patient 7 has Autistic Spectrum Disorder (ASD) and microcephaly.

Patient History

@ 12 months - Patient 7 presented with seizures.

Patient 7 developed additional seizure types including: focal seizures with/without generalization, generalized tonic/clonic/tonic-clonic seizures, myoclonic seizures, and hypomotor seizures.

Patient 7 was on two antiepileptic drugs at most recent followup 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:SLC9A6

Variant:Hemizygous splice site NM_001042537.1 c. 794-2A>G was assessed by the authors to be likely pathogenic.

HGVS:Not provided

ClinVarID:Not found

CAID:CA414750320

gnomAD:Not found

MultipleGeneVariants:Not provided

Case#: case_Kiyota_2018, female,1 yo (onset), Japanese ancestry reported

DiseaseAssertion: APDS + 22q13 deletion syndrome

FamilyInfo: de novo

CasePresentingHPOs: (HP:0001973, HP:0000969, HP:0011134, HP:0000123, HP:0000093, HP:0003073, HP:0004431, HP:0003493, HP:0020151, HP:0033604, HP:0001263, HP:0001290, HP:0000729, HP:0002463, HP:0001249, HP:0007021, HP:0012433

ITP systemic edema mild fever lupus nephritis proteinuria hypoalbuminemia decreased complement levels antinuclear antibody double strand DNA antibody wire-loop lesions in glomeruli delayed psychmotor development hypotonia autistic features language delay intellectual disability reduced sensitivity to pain poor social functioning

CaseHPOFreeText: positive staining for IgG, IgA, IgM, C3 and C1q and electron-dense deposits observed through renal biopsy, along with wire-loop lesions

CaseNotHPOs: (HP:0030882, 0010783, HP:0030880) coronary aneurysm butterfly erythema Raynaud's phenomenon

CaseNotHPOFreeText: dysmorphic features

CasePreviousTesting: G-band karyotyping + whole genome SNP microarray revealed 22q13 deletion syndrome

GenotypingMethod: WES

PreviouslyPublished:

Variant: NM_005026.3:c.1534C > T; p.(Arg512Trp)

ClinVarID: 1347382

CAID: CA577258

gnomAD: v2.1.1 Grpmax 0.00007392 (4/18252 alleles) East Asian population

SupplementalData:

Case#: Hui_2016, female, 2 yo (presentation), origin NR

DiseaseAssertion: APDS

FamilyInfo: variants verified in patient's parents, found to be de novo. It is unclear if case 2 and case 4 are related or unrelated.

CasePresentingHPOs: recurrent respiratory infections, enlargement of lymph node, hepatosplenomegaly, decreased number of native CD4 + T cells, inverted CD4 + /CD8 + T cell ratio and increased IgM, decreased IgA, decreased IgG,

HP:0002205, HP:0002716, HP:0001433, HP:0002720, HP:0032218, HP:0033222, HP:0002720, HP:0003496

CaseHPOFreeText: cytomegalovirus (CMV) or Epstein-Barr virus (EBV) viremia

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

GenotypingMethod: WGS

PreviouslyPublished: NR

Variant: HOMOZYGOUS 3061G>A (E1021K)

ClinVarID: 88675

CAID: N/A

gnomAD: not found in v2.1.1

SupplementalData: unknown

Note: Full access to article denied. Info in annotation gathered from abstract. Also, please be advised the curator translated the article from Chinese to English, and mistranslations are possible.

Case#: 34 year-old Chinese male.

DiseaseAssertion: HAE-C1INH Type 1.

FamilyInfo: Family history of edema (mother passed away due to laryngeal edema, older sister experienced buttock swelling after prolonged sitting, maternal uncle experienced episodic abdominal pain and unilateral upper-limb swelling). Family testing for serum C4 and C1INH concentration and C1INH functional activity indicate that proband’s maternal uncle and asymptomatic daughter exhibit low values for all three of these biochemical markers, consistent with Type 1 HAE. The proband’s daughter and maternal uncle also tested positive for the variant identified in the proband. Pedigree included in figures.

ParentalTesting: Mother passed away before study. Father tested for C4 and C1INH concentration and C1INH function with all values falling in normal ranges.

CasePresentingHPOs: Edema (HP:0000969), Edema of the dorsum of hands (HP:0007514), Edema of the upper limbs (HP:0010742), Non-pitting edema (HP:6000507), Abdominal pain (HP:0002027)

CasePhenotypeFreeText: Onset at approximate age of 26. Episodes of localized edema of limbs, skin, and buttocks lasting two to three days regardless of treatment. Episodes became more frequent at age 34 and were accompanied by abdominal pain triggered by fatigue. Non-pitting edema of right hand observed on physical examination.. The proband’s C4 level was 0.02 g/L (reference range: 0.1–0.4 g/L), C1INH concentration was 0.07 g/L (reference range: 0.21–0.39 g/L), and C1INH functional activity was 4.3% (reference range: ≥68.0%).

CaseNotHPOs: N/A

CaseNotPhenotypeFreeText: N/A

CasePreviousTesting: N/A

GenotypingMethod: PCR amplification with Sanger sequencing.

Variant: NM_000062:c.1067T>A p.(Val356Glu)

LegacyVariant: N/A

ClinVar: N/A

CAID: CA380702482

gnomAD: N/A

MultipleGeneVariants: N/A

PreviouslyPublished: N/A

AdditionalInfo: N/A

-Gene: DICER1 -PMID: 29343557 -Inheritance Pattern: DICER1 is inherited as an autosomal dominant condition with decreased penetrance -Disease Entity: earlier onset disease, multisite disease, 0-2 site disease, cystic lung disease, familial disease, bilateral disease, stage IA/IB, bilateral disease -mutation: germline loss-of-function mutation, missense mutation, Intronic mutations, hotspot mutation, second somatic mutation, truncating mutations, biallelic mutation -zygosity: heterozygosity -Family History: -testing should be considered for those with a family history of DICER1-associated conditions so that appropriate surveillance can be undertaken. -Individuals at 50% risk of a germline pathogenic variant based on family history who do not pursue genetic testing should follow surveillance guidelines as -if they have a DICER1 mutation unless/until genetic testing confirms that they did not inherit the familial mutation When a pulmonary cyst is identified in a young child with a pathogenic germline -DICER1 variant or family history of a DICER1-associated condition, it should be assumed to be Type I PPB until proven otherwise

Other Information: -Case: Risk for most DICER1-associated neoplasms is highest in early childhood and decreases in adulthood -affected phenotype may simply result from probabilities of generating the characteristic “loss-of-function plus hotspot” two hit typical of a DICER1 syndrome neoplasm. -Caseprevioustesting: presymptomatic testing of a minor child, should be discussed and factored into the decision process, as some individuals may choose, and have the right to choose, not to know their/their child’s genetic status. -gnomAD: n/a