Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations
Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations
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
e86940
Tapper, William J.
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Foulds, Nicola
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Cross, Nicholas C. P.
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Aranaz, Paula
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Score, Joannah
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Hidalgo-Curtis, Claire
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Robinson, David O.
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Gibson, Jane
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Ennis, Sarah
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Temple, I. Karen
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Collins, Andrew
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31 January 2014
Tapper, William J.
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Foulds, Nicola
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Cross, Nicholas C. P.
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Aranaz, Paula
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Score, Joannah
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Hidalgo-Curtis, Claire
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Robinson, David O.
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Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Ennis, Sarah
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Temple, I. Karen
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Collins, Andrew
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Tapper, William J., Foulds, Nicola, Cross, Nicholas C. P., Aranaz, Paula, Score, Joannah, Hidalgo-Curtis, Claire, Robinson, David O., Gibson, Jane, Ennis, Sarah, Temple, I. Karen and Collins, Andrew
(2014)
Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations.
PLoS ONE, 9 (1), .
(doi:10.1371/journal.pone.0086940).
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
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Published date: 31 January 2014
Organisations:
Human Development & Health
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Local EPrints ID: 361939
URI: http://eprints.soton.ac.uk/id/eprint/361939
ISSN: 1932-6203
PURE UUID: b6449d5a-5c61-4336-b8a0-df16fcfc6a3d
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Date deposited: 07 Feb 2014 15:05
Last modified: 15 Mar 2024 03:17
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Author:
Nicola Foulds
Author:
Paula Aranaz
Author:
Joannah Score
Author:
Claire Hidalgo-Curtis
Author:
David O. Robinson
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