A De novo Loss-of-Function Mutation in PAFAH1B1 Identified in a Single Case with Agyria–Pachygyria Complex

Abstract

AbstractTo identify genetic causes in affected infants with abnormalities of brain development, including malformations of cortical development–associated neuropsychological disorders, affected infants were recruited based on their clinical examination and cranial imaging studies. Trio whole-exome sequencing (WES), bioinformatic analysis, and genotype–phenotype correlations were performed for 20 affected subjects to identify candidate mutations, followed by Sanger sequencing for further verification. In the present study, we identified a de novo heterozygous mutation (c.265C > T, p.R89*) of the PAFAH1B1 gene in the affected child with epilepsy, speech impairment, and cerebral palsy. The mutation was predicted to be a null loss-of-function allele, which was not found in ExAC and the Chinse Han Exome Sequences databases. Magnetic resonance imaging of the brain demonstrated bilateral parieto-occipital and temporal lissencephaly as well as frontal partial pachygyria in the affected child. This is the first case with agyria–pachygyria complex due to a nonsense mutation in the Chinese population identified by a trio WES approach.