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Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation
- Source :
- NPJ genomic medicine, vol 1, iss 1, Ge, X, Gong, H, Dumas, K, Litwin, J, Phillips, J J, Waisfisz, Q, Weiss, M M, Hendriks, Y, Stuurman, K E, Nelson, S F, Grody, W W, Lee, H, Kwok, P-Y & Shieh, J T C 2016, ' Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation ', NPJ GENOMIC MEDICINE, vol. 1 . https://doi.org/10.1038/npjgenmed.2016.36, NPJ GENOMIC MEDICINE, 1. Nature Publishing Group, NPJ Genomic Medicine
- Publication Year :
- 2016
- Publisher :
- eScholarship, University of California, 2016.
-
Abstract
- Genomic sequence interpretation can miss clinically relevant missense variants for several reasons. Rare missense variants are numerous in the exome and difficult to prioritise. Affected genes may also not have existing disease association. To improve variant prioritisation, we leverage population exome data to identify intragenic missense-depleted regions (MDRs) genome-wide that may be important in disease. We then use missense depletion analyses to help prioritise undiagnosed disease exome variants. We demonstrate application of this strategy to identify a novel gene association for human brain malformation. We identified de novo missense variants that affect the GDP/GTP-binding site of ARF1 in three unrelated patients. Corresponding functional analysis suggests ARF1 GDP/GTP-activation is affected by the specific missense mutations associated with heterotopia. These findings expand the genetic pathway underpinning neurologic disease that classically includes FLNA. ARF1 along with ARFGEF2 add further evidence implicating ARF/GEFs in the brain. Using functional ontology, top MDR-containing genes were highly enriched for nucleotide-binding function, suggesting these may be candidates for human disease. Routine consideration of MDR in the interpretation of exome data for rare diseases may help identify strong genetic factors for many severe conditions, infertility/reduction in reproductive capability, and embryonic conditions contributing to preterm loss.
- Subjects :
- 0301 basic medicine
Exome sequencing
Population
Disease
Biology
Article
03 medical and health sciences
0302 clinical medicine
ARF1
MDR
Genetics
Missense mutation
FLNA
2.1 Biological and endogenous factors
Aetiology
education
Molecular Biology
Gene
Exome
Genetics (clinical)
variant prioritization
education.field_of_study
nucleotide-binding
brain malformation
Human Genome
GDP/GTP
RAS superfamily
030104 developmental biology
Good Health and Well Being
Neurological
missense-depletion
Ras superfamily
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 20567944
- Database :
- OpenAIRE
- Journal :
- NPJ genomic medicine, vol 1, iss 1, Ge, X, Gong, H, Dumas, K, Litwin, J, Phillips, J J, Waisfisz, Q, Weiss, M M, Hendriks, Y, Stuurman, K E, Nelson, S F, Grody, W W, Lee, H, Kwok, P-Y & Shieh, J T C 2016, ' Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation ', NPJ GENOMIC MEDICINE, vol. 1 . https://doi.org/10.1038/npjgenmed.2016.36, NPJ GENOMIC MEDICINE, 1. Nature Publishing Group, NPJ Genomic Medicine
- Accession number :
- edsair.doi.dedup.....b2132edc64cfb2001cdb4347c990df42