A new missense mutation found in the FLNA gene in a family with bilateral periventricular nodular heterotopia (BPNH) alters the splicing process.

We describe the clinical and molecular evaluation of two patients, mother and daughter (proband), with bilateral periventricular nodular heterotopia (BPNH). The clinical evaluation revealed a more severe phenotype in the proband, with mental retardation and seizures. Imaging studies showed bilateral periventricular nodules in both patients. We identified a novel mutation, c.987G-->C mutation in exon 6 of the Filamin A (FLNA) gene in the genomic DNA of both patients. Complementary DNA (cDNA) sequencing revealed the maintenance of intron 6 in the mutated allele. Bioinformatics analysis indicates that the mutation identified in both patients probably destroyed the intron 6 donor-splicing site, which is likely to introduce a premature stop codon resulting in a truncated FLNA protein. In addition, X-chromosome inactivation studies in DNA of blood cells revealed a skewed pattern in the proband, and real time quantitative polymerase chain reaction (PCR) showed a higher expression of the mutated allele in the proband compared to that of the mother. This variation in expression of the mutated allele may be responsible for the differences in the clinical manifestations observed in both patients.