Objective: To explore the genetic basis for a child featuring complex cortical dysplasia and other brain malformations (CDCBM3).
Methods: Genomic DNA was extracted from peripheral blood samples from the patient and his parents. Whole exome sequencing (WES) was carried out for the family trio. Suspected variant was verified by Sanger sequencing.
Results: The proband, a 1-year-and-2-month old Chinese boy, had presented with motor developmental delay, lissencephaly, severe cognitive impairments, absent speech and congenital laryngomalacia. WES revealed that he has harbored a heterozygous missense variant of the KIF2A gene, namely NM_001098511.2: c.952G>A, p.Gly318Arg (GRCh37/hg19). The highly conserved residue is located around the ATP nucleotide-binding pocket in the kinesin motor domain (PM1). The variant was not found in the Genome Aggregation Database and the 1000 Genomes Project (PM2), and was predicted to be deleterious on the gene product by multiple in silico prediction tools (PP3). This variant was unreported previously and was de novo in origin (PS2). Based on the ACMG guidelines, it was categorized as likely pathogenic (PS2+PM1+PM2+PP3). Furthermore, the congenital laryngomalacia found in our patient was absent in previously reported CDCBM3 cases.
Conclusion: The novel variant of the KIF2A gene probably underlay the disorders in the proband. Above finding has expanded the phenotypic and mutational spectrum of CDCBM3.