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Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.

ABSTRACT: Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation.To increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients. We prioritized the candidate genes, and followed up 31 variants in this prioritized subset of candidate genes.Twenty-nine genotypes in known genes for EE (19) or related diseases (10), dominant as well as recessive or X-linked, were classified as likely pathogenic variants. Among those, likely pathogenic de novo variants were found in EE genes that act dominantly, including the recently identified genes EEF1A2, KCNB1 and the X-linked gene IQSEC2. A de novo frameshift variant in candidate gene HNRNPU was the only de novo variant found among the followed-up candidate genes, and the patient's phenotype was similar to a few recent publications.Mutations in genes described in OMIM as, for example, intellectual disability gene can lead to phenotypes that get classified as EE in the clinic. We confirmed existing literature reports that de novo loss-of-function HNRNPUmutations lead to severe developmental delay and febrile seizures in the first year of life.

SUBMITTER: de Kovel CG

PROVIDER: S-EPMC5023942 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.

de Kovel Carolien G F CG Brilstra Eva H EH van Kempen Marjan J A MJ Van't Slot Ruben R Nijman Isaac J IJ Afawi Zaid Z De Jonghe Peter P Djémié Tania T Guerrini Renzo R Hardies Katia K Helbig Ingo I Hendrickx Rik R Kanaan Moine M Kramer Uri U Lehesjoki Anna-Elina E AE Lemke Johannes R JR Marini Carla C Mei Davide D Møller Rikke S RS Pendziwiat Manuela M Stamberger Hannah H Suls Arvid A Weckhuysen Sarah S Koeleman Bobby P C BP

Molecular genetics & genomic medicine 20160730 5

<h4>Background</h4>Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation.<h4>Methods</h4>To increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients. We prioriti ...[more]

PMID: 27652284

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Project description:A major goal of maize genomic research is to identify sequence polymorphisms responsible for phenotypic variation in traits of economic importance. Large-scale detection of sequence variation is critical for linking genes, or genomic regions, to phenotypes. However, due to its size and complexity, it remains expensive to generate whole genome sequences of sufficient coverage for divergent maize lines, even with access to next generation sequencing (NGS) technology. Because methods involving reduction of genome complexity, such as genotyping-by-sequencing (GBS), assess only a limited fraction of sequence variation, targeted sequencing of selected genomic loci offers an attractive alternative. We therefore designed a sequence capture assay to target 29 Mb genomic regions and surveyed a total of 4,648 genes possibly affecting biomass production in 21 diverse inbred maize lines (7 flints, 14 dents). Captured and enriched genomic DNA was sequenced using the 454 NGS platform to 19.6-fold average depth coverage, and a broad evaluation of read alignment and variant calling methods was performed to select optimal procedures for variant discovery. Sequence alignment with the B73 reference and de novo assembly identified 383,145 putative single nucleotide polymorphisms (SNPs), of which 42,685 were non-synonymous alterations and 7,139 caused frameshifts. Presence/absence variation (PAV) of genes was also detected. We found that substantial sequence variation exists among genomic regions targeted in this study, which was particularly evident within coding regions. This diversification has the potential to broaden functional diversity and generate phenotypic variation that may lead to new adaptations and the modification of important agronomic traits. Further, annotated SNPs identified here will serve as useful genetic tools and as candidates in searches for phenotype-altering DNA variation. In summary, we demonstrated that sequencing of captured DNA is a powerful approach for variant discovery in maize genes.

Dataset Information

Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.

Publications

Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients.

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