KIF6

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: LiferaOmics

Genetic evidence – Published PMID: 30475797 – Reports one consanguineous family with a neurodevelopmental disorder characterized by global developmental delay/intellectual disability, macrocephaly, hypotonia, and EEG abnormalities, harboring a homozygous truncating frameshift variant in KIF6 (c.1193delT; p.Leu398Glnfs*2). Parents were first cousins and confirmed heterozygous carriers; an unaffected sibling was also heterozygous. Phenotype is consistent with an autosomal recessive neurodevelopmental disorder. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguineous so −0.5 applied) = (1.5 − 0.5) = 1.0; segregation (parental carrier confirmation; one additional heterozygous unaffected sibling; conservative) = 0.5; case-control = 0; PMID: 30475797 total = 1.5. Published genetic evidence total = 1.5/12 Genetic evidence – Our cases Family 1 – One proband. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5) = (1.5 − 0.5) = 1.0; segregation = 0; case-control = 0; Family 1 total = 1.0. Family 2 – One proband. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity unknown so no deduction applied) = 1.5;segregation = 0; case-control = 0; Family 2 total = 1.5. Our cases total = (1.0 + 1.5) = 2.5/12 Total genetic evidence (published + our cases) 1.5 + 2.5 = 4.0/12 Experimental evidence – Published PMID: 30475797 – Functional studies demonstrate that KIF6 loss-of-function disrupts ependymal cilia structure and cerebrospinal fluid dynamics. A mouse model harboring a C-terminal truncating mutation developed progressive hydrocephalus with ependymal cilia defects; zebrafish models showed ventricular dilation and reduced cilia. These findings support a loss-of-function mechanism consistent with neurodevelopmental pathology. Model systems evidence (Expression and vertebrate models recapitulating relevant neurological phenotype) = 2.5; experimental total = 2.5. Experimental evidence total = 2.5/6 Overall score Overall score = 4.0 + 2.5 = 6.5/18