Cortical Dysplasia, Complex, with Other Brain Malformations 3 via the KIF2A Gene

KIF2A-related cortical dysplasia, complex, with other brain malformations 3 is a rare neurological disorder with onset as early as a few months old. The major symptoms include lissencephaly and microcephaly (variable congenital and postnatal microcephaly, up to −5 SD), seizures, spastic tetraplegia, and delayed psychomotor development. The minor features include intrauterine growth retardation, hypotonia, mild dysmorphic facial features, and nystagmus. MRI image analysis shows pachygyria, agyria, thick cortex, subcortical band heterotopia, thin corpus callosum, and more (Cavallin et al. 2017. PubMed ID: 27747449).  

As cortical dysplasia can be caused by defects in many genes with variable and overlapping presentations, it is difficult to diagnose by clinical manifestation and image studies only. An accurate molecular diagnosis is critical for treatment, prognosis, and prediction of recurrence risk as well as future family planning.

KIF2A-related cortical dysplasia, complex, with other brain malformation 3 is inherited in an autosomal dominant manner. Pathogenic variants in KIF2A include missense and nonsense. A large deletion has also been reported in the KIF2A locus (Human Gene Mutation Database). De novo variants are common in this disorder (Cavallin et al. 2017. PubMed ID: 27747449).

KIF2A encodes kinesin heavy chain member 2A, which is from the kinesin-13 family, implicated in the regulation of microtubule plus-end dynamics. KIF2A protein is expressed in the developing cerebral cortex. The proteins in the kinesin superfamily play important roles in neuronal function and development via interactions with microtubules (Homma et al. 2003. PubMed ID: 12887924). Functional studies revealed that pathogenic variants in the KIF2A alter cortical neuronal positioning, change neural progenitor proliferation, impair mitotic spindle integrity and mitotic progression, and lead to defects of interneuron migration (Broix et al. 2018. PubMed ID: 29077851). A conditional knock-in mouse model with a heterozygous KIF2A: p.His321Asp had malformations of cortical development. Neuroanatomical anomalies and microcephaly associated with abnormal behavior and susceptibility to seizures were observed in the model, which correlates with the human phenotype (Gilet et al. 2020. PubMed ID: 31919497). KIF2A is relative intolerant to missense and loss-of-function variants (Genome Aggregation Database). Overall, KIF2A has been cited as a non-essential gene for growth of human tissue culture cells (Online Gene Essentiality).

Pathogenic variants in KIF2A are a rare causes of cortical dysplasia. In 162 patients with cortical dysplasia, two cases had a pathogenic variant in KIF2A (Poirier et al. 2013. PubMed ID: 23603762).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the KIF2A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).