KCTD3

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: LiferaOmics

Genetic evidence – Published PMID: 29406573 – Reports four consanguineous families (7 affected individuals total) with developmental and epileptic encephalopathy characterized by global developmental delay, hypotonia, early-onset seizures, and consistent posterior fossa/cerebellar abnormalities, harboring homozygous loss-of-function variants in KCTD3 that fully segregated within families (multiple affected individuals per family; carrier parents confirmed). Case-level (biallelic predicted null in AR model; homozygous scored once per family; all consanguineous so −0.5 applied) = 4 families × (1.5 − 0.5) = 4.0; segregation (additional affected individuals beyond proband across families with parental carrier confirmation; conservative) = 1.0; case-control = 0; PMID: 29406573 total = 5.0. PMID: 25558065 – Reports an independent AR family with psychomotor retardation and seizures and a homozygous frameshift variant; phenotype compatible with DEE spectrum. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity unknown so no deduction applied) = 1.5; segregation = 0; case-control = 0; PMID: 25558065 total = 1.5. PMID: 32552793 – Reports an independent AR family with microcephaly, cerebral white matter abnormality, intellectual disability, and compatible DEE phenotype with the same homozygous frameshift variant. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity unknown so no deduction applied) = 1.5; segregation = 0; case-control = 0; PMID: 32552793 total = 1.5. PMID: 33726816 – Reports an independent AR case with homozygous nonsense variant in and compatible developmental and epileptic encephalopathy phenotype. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity unknown so no deduction applied) = 1.5; segregation = 0; case-control = 0; PMID: 33726816 total = 1.5. PMID: 37550298 – Reports a developmental and epileptic encephalopathy case with a biallelic nonsense variant due to paternal uniparental isodisomy of chromosome 1; mechanism consistent with AR loss-of-function. Case-level (biallelic predicted null in AR model; homozygous via UPD; non-consanguineous) = 1.5; segregation = 0; case-control = 0; PMID: 37550298 total = 1.5. Published genetic evidence total = (5.0 + 1.5 + 1.5 + 1.5 + 1.5) = 11.0/12 Genetic evidence – Our cases Family 1 – One proband (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5) = 1.0; segregation = 0; case-control = 0; Family 1 total = 1.0. Family 2 – One proband (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5) = 1.0; segregation = 0; case-control = 0; Family 2 total = 1.0. Family 3 – One proband (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5) = 1.0; segregation (affected sib counted as segregation; conservative) = 0.5; case-control = 0; Family 3 total = 1.5. Our cases total = 3.5/12 Total genetic evidence (published + our cases) 11.0 + 3.5 = 14.5 (capped at 12.0/12) Experimental evidence – Published Functional studies demonstrate that KCTD3 interacts with HCN3 and modulates neuronal excitability, supporting biological plausibility for epilepsy mechanisms. Gene function / biochemical function evidence = 0.5; experimental total = 0.5. Experimental evidence total = 0.5/6 Overall score Overall score = 12.0 + 0.5 = 12.5 First report: PMID: 25558065 (2015) Additional independent families published in subsequent years (2018; 2020; 2021; 2023).

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia