Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation

Xiaoyan Ge; Henry Gong; Kevin Dumas; Jessica Litwin; Joanna J Phillips; Quinten Waisfisz; Marjan M Weiss; Yvonne Hendriks; Kyra E Stuurman; Stanley F Nelson; Wayne W Grody; Hane Lee; Pui-Yan Kwok; Joseph Tc Shieh

doi:10.1038/npjgenmed.2016.36

Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation

NPJ Genom Med. 2016:1:16036. doi: 10.1038/npjgenmed.2016.36. Epub 2016 Oct 5.

Authors

Xiaoyan Ge^{1

2}, Henry Gong^{1

2}, Kevin Dumas^{1

2}, Jessica Litwin^{3

4}, Joanna J Phillips^{5

6}, Quinten Waisfisz⁷, Marjan M Weiss⁷, Yvonne Hendriks⁷, Kyra E Stuurman⁷, Stanley F Nelson⁸, Wayne W Grody⁹, Hane Lee¹⁰, Pui-Yan Kwok^{2

11

12}, Joseph Tc Shieh^{1

2}

Affiliations

¹ Department of Pediatrics, Division of Medical Genetics, University of California San Francisco, San Francisco, CA, USA.
² Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
³ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
⁴ Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Neurologic Surgery, University of California San Francisco, San Francisco, CA, USA.
⁶ Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
⁸ Departments of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics, Divisions of Medical Genetics and Molecular Diagnostics, University of California Los Angeles, Los Angeles, CA, USA.
⁹ Department of Pathology and Laboratory Medicine and Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA.
¹⁰ Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.
¹² Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.

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.

Keywords: ARF1; Exome sequencing; GDP/GTP; MDR; RAS superfamily; brain malformation; missense-depletion; nucleotide-binding; variant prioritization.

Abstract

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