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Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations
- Source :
- PLoS ONE, Vol 9, Iss 1, p e86940 (2014), PLoS ONE
- Publication Year :
- 2014
- Publisher :
- Public Library of Science (PLoS), 2014.
-
Abstract
- 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.
- Subjects :
- Male
Genetic Screens
Vascular Malformations
Gene Identification and Analysis
lcsh:Medicine
Phosphatidylinositol 3-Kinases
Fatal Outcome
Gene Frequency
Exome
Megalencephaly
Genome Sequencing
lcsh:Science
Exome sequencing
Genetics
Multidisciplinary
Genomics
Syndrome
3. Good health
Phenotype
Neurology
Mutation (genetic algorithm)
Medicine
Female
medicine.symptom
Research Article
Hydrocephalus
Genotype
Class I Phosphatidylinositol 3-Kinases
Biology
Polymorphism, Single Nucleotide
Molecular Genetics
Germline mutation
Genome Analysis Tools
Genetic Mutation
medicine
Humans
Genetic Predisposition to Disease
Allele
Allele frequency
lcsh:R
Macrocephaly
Computational Biology
Infant
Human Genetics
Sequence Analysis, DNA
medicine.disease
Capillaries
Polydactyly
Genetics of Disease
Mutation
lcsh:Q
Syndactyly
Proto-Oncogene Proteins c-akt
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 9
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....7db3add2af5354c73e414319d2b9ca10