KIF26A

Inheritance Pattern: AR

Disease ID:MONDO:0859332

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0859332

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0859332

Submitter: Baylor College of Medicine Research Center

Inheritance Pattern: AR

Disease ID:MONDO:0859332

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0000904

Submitter: ClinGen

KIF26A was first reported in relation to autosomal recessive congenital brain malformations in 2022 (Qian et al., PMID: 36228617) and with autosomal recessive congenital hydrocephalus with megacolon later that year (Almannai et al, PMID 36564622). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no significant difference in molecular mechanism, inheritance pattern or brain malformation phenotype between these conditions. Therefore, the these phenotypes have been lumped and curated together as autosomal recessive complex cortical dysplasia with other brain malformations (http://purl.obolibrary.org/obo/MONDO_0000904). Eight variants (5 missense, 3 frameshift) that have been reported in 7 probands in 2 publications (PMIDs: 36228617, 36564622) are included in this curation. Functional evidence supports a damaging impact for 4 of the missense variants, one of which is recurrent and seen in 3 of the 7 probands. Homozygous cases are present in gnomADv4.0.0 for 2 of these missense variants, raising the possibility of incomplete penetrance and/or variable expressivity. Notably, the three reported cases with loss of function variants have reported enteric involvement, while this has not been described in cases with missense variants. The mechanism of pathogenicity appears to loss of function. This gene-disease relationship is also supported by experimental evidence (PMID: 36228617). Expression analysis shows expression in all cortical regions throughout embryonic and postnatal development, with preferential expression in migrating excitatory neurons in the developing cerebral cortex. Kif26a depletion in the developing mouse brain disrupts the radial migration of cortical excitatory neurons and impairs neuronal localization, morphology, and corpus callosum development, but does not impact overall morphology of the corpus callosum. KIF26A knock-out hiPSC show shorter neurites and decreased migration from neurospheres than controls iPSC cells, which is rescued with exogenous KIF26A. In summary, there is strong evidence to support the relationship between KIF26A and autosomal recessive complex cortical dysplasia with other brain malformations. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date 12 March 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0859332

Submitter: Ambry Genetics