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Two megalencephaly (MEG) syndromes, megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyriapolydactyly-hydrocephalus (MPPH), have recently been defined on the basis of physical and neuroimaging features. Subsequently, exome sequencing of ten MEG cases identified  de-novo  postzygotic mutations in  PIK3CA  which cause MCAP and  de-novo  mutations in  AKT  and  PIK3R2  which cause MPPH. Here we present findings from exome sequencing three unrelated megalencephaly patients which identified a causal  PIK3CA  mutation in two cases and a causal  PIK3R2  mutation in the third case. However, our patient with the  PIK3R2  mutation which is considered to cause MPPH has a marked bifrontal band heterotopia which is a feature of MCAP. Furthermore, one of our patients with a  PIK3CA  mutation lacks syndactyly/polydactyly which is a characteristic of MCAP. These findings suggest that the overlap between MCAP and MPPH may be greater than the available studies suggest. In addition, the  PIK3CA  mutation in one of our patients could not be detected using standard exome analysis because the mutation was observed at a low frequency consistent with somatic mosaicism. We have therefore investigated several alternative methods of exome analysis and demonstrate that alteration of the initial allele frequency spectrum (AFS), used as a prior for variant calling in samtools, had the greatest power to detect variants with low mutant allele frequencies in our 3 MEG exomes and in simulated data. We therefore recommend non-default settings of the AFS in combination with stringent quality control when searching for causal mutation(s) that could have low levels of mutant reads due to post-zygotic mutation.

Megalencephaly Syndromes: Exome Pipeline Strategies for Detecting Low-Level Mosaic Mutations