Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3

Abstract

Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8‐year‐old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole‐exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously‐reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum “KIF2A syndrome” with variable severity.

Inhibitory synapse dysfunction and epileptic susceptibility associated with KIF2A deletion in cortical interneurons

“…Patients with missense mutations in KIF2A exhibit so called cortical dysplasia complex with other brain malformations (CDCBM), a type of MCD characterized by posterior agyria/pachygyria, microcephaly and severe motor dysfunction; and most of them suffer childhood epilepsy ( Poirier et al, 2013 ; Tian et al, 2016 ; Cavallin et al, 2017 ; Costain et al, 2019 ; Hatano et al, 2021 ). Pathogenic variants of KIF2A alter the subcellular localization of KIF2A, thus affecting its ability to bind MT ( Poirier et al, 2013 ; Broix et al, 2018 ; Gilet et al, 2020 ).…”

“…It is believed to depolymerize MT in an ATP-dependent manner and regulate MT dynamics ( Desai et al, 1999 ; Trofimova et al, 2018 ; Ruiz-Reig et al, 2022 ). In humans, single de novo missense mutations in KIF2A were found in patients with early-life epilepsy, posterior pachygyria, microcephaly, and partial agenesis of corpus callosum ( Poirier et al, 2013 ; Tian et al, 2016 ; Cavallin et al, 2017 ; Hatano et al, 2021 ). Analysis of knockout mice revealed that the protein is necessary for neuronal migration, and axonal elongation, branching, and pruning ( Homma et al, 2003 ; Maor-Nof et al, 2013 ).…”

KIF2A deficiency causes early-onset neurodegeneration

“…Postnatal deletion of KIF2A confirmed that KIF2A, independent of its role during development, is essential for neuronal survival. It is worth mentioning that microcephaly due to KIF2A mutations in patients worsens postnatally ( 25 ), and in some cases, patients are diagnosed with secondary microcephaly (DECIPHER patient 280143, c.1762G > T, p.Val588Phe), suggesting that these mutations affect postnatal processes such as neuronal maturation or survival and not only embryonic development.…”

“…In humans, de novo mutations in KIF2A have been linked to a wide variety of clinical manifestations depending on the affected domain of the protein. Mutations in the nucleotide-binding domain were associated with malformations of cortical development, including microcephaly, lissencephaly, and partial agenesis of the corpus callosum (CC; 22 – 25 ). Variants in the motor domain were associated with epilepsy, and variants in other domains were associated with autism spectrum disorder ( 25 – 27 ).…”

“…Mutations in the nucleotide-binding domain were associated with malformations of cortical development, including microcephaly, lissencephaly, and partial agenesis of the corpus callosum (CC; 22 – 25 ). Variants in the motor domain were associated with epilepsy, and variants in other domains were associated with autism spectrum disorder ( 25 – 27 ). Finally, overexpression and one rare variant were associated with Alzheimer’s disease (AD) ( 28 , 29 ).…”