In trans variant calling reveals enrichment for compound heterozygous variants in genes involved in neuronal development and growth

Allison J Cox; Fillan Grady; Gabriel Velez; Vinit B Mahajan; Polly J Ferguson; Andrew Kitchen; Benjamin W Darbro; Alexander G Bassuk

doi:10.1017/S0016672319000065

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In trans variant calling reveals enrichment for compound heterozygous variants in genes involved in neuronal development and growth

Journal article

Open access

Peer reviewed

In trans variant calling reveals enrichment for compound heterozygous variants in genes involved in neuronal development and growth

Allison J Cox, Fillan Grady, Gabriel Velez, Vinit B Mahajan, Polly J Ferguson, Andrew Kitchen, Benjamin W Darbro and Alexander G Bassuk

Genetics research, Vol.101, pp.e8-e8

06/13/2019

DOI: 10.1017/S0016672319000065

PMCID: PMC7045018

PMID: 31190668

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Abstract

Compound heterozygotes occur when different variants at the same locus on both maternal and paternal chromosomes produce a recessive trait. Here we present the tool VarCount for the quantification of variants at the individual level. We used VarCount to characterize compound heterozygous coding variants in patients with epileptic encephalopathy and in the 1000 Genomes Project participants. The Epi4k data contains variants identified by whole exome sequencing in patients with either Lennox-Gastaut Syndrome (LGS) or infantile spasms (IS), as well as their parents. We queried the Epi4k dataset (264 trios) and the phased 1000 Genomes Project data (2504 participants) for recessive variants. To assess enrichment, transcript counts were compared between the Epi4k and 1000 Genomes Project participants using minor allele frequency (MAF) cutoffs of 0.5 and 1.0%, and including all ancestries or only probands of European ancestry. In the Epi4k participants, we found enrichment for rare, compound heterozygous variants in six genes, including three involved in neuronal growth and development - PRTG (p = 0.00086, 1% MAF, combined ancestries), TNC (p = 0.022, 1% MAF, combined ancestries) and MACF1 (p = 0.0245, 0.5% MAF, EU ancestry). Due to the total number of transcripts considered in these analyses, the enrichment detected was not significant after correction for multiple testing and higher powered or prospective studies are necessary to validate the candidacy of these genes. However, PRTG, TNC and MACF1 are potential novel recessive epilepsy genes and our results highlight that compound heterozygous variants should be considered in sporadic epilepsy.

Gene Frequency - genetics

Prospective Studies

Tenascin - genetics

Genes, Recessive - genetics

Humans

Epilepsy - metabolism

Infant

Male

Spasms, Infantile - genetics

Lennox Gastaut Syndrome - genetics

Exome

Adult

Epilepsy - genetics

Female

Microfilament Proteins - genetics

Infant, Newborn

Lennox Gastaut Syndrome - metabolism

Genetic Predisposition to Disease - genetics

Membrane Proteins - genetics

Spasms, Infantile - metabolism

Phenotype

Alleles

Heterozygote

Genetic Variation - genetics

Mutation

Sequence Analysis, DNA - methods

Details

Title: Subtitle: In trans variant calling reveals enrichment for compound heterozygous variants in genes involved in neuronal development and growth
Creators: Allison J Cox - Department of Pediatrics,The University of Iowa,Iowa City,IA,USA
Fillan Grady - Medical Scientist Training Program,University of Iowa,Iowa City,IA,USA
Gabriel Velez - Medical Scientist Training Program,University of Iowa,Iowa City,IA,USA
Vinit B Mahajan - Omics Laboratory,Department of Ophthalmology,Byers Eye Institute,Stanford University,Palo Alto,CA,USA
Polly J Ferguson - Department of Pediatrics,The University of Iowa,Iowa City,IA,USA
Andrew Kitchen - Department of Anthropology,The University of Iowa,Iowa City,IA,USA
Benjamin W Darbro - Department of Pediatrics,The University of Iowa,Iowa City,IA,USA
Alexander G Bassuk - Department of Pediatrics,The University of Iowa,Iowa City,IA,USA
Resource Type: Journal article
Publication Details: Genetics research, Vol.101, pp.e8-e8
DOI: 10.1017/S0016672319000065
PMID: 31190668
PMCID: PMC7045018
NLM abbreviation: Genet Res (Camb)
ISSN: 0016-6723
eISSN: 1469-5073
Publisher: England
Grant note: T32 GM008629 / NIGMS NIH HHS R01 AR059703 / NIAMS NIH HHS R01 NS098590 / NINDS NIH HHS T32 GM082729 / NIGMS NIH HHS T32 GM007337 / NIGMS NIH HHS
Language: English
Date published: 06/13/2019
Academic Unit: Neurology; Anthropology; International Programs; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Rheumatology, Allergy, and Immunology; Neurology (Pediatrics)
Record Identifier: 9984070323702771

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