title: Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing.
abstract: Moyamoya disease (MMD) is a rare disorder characterized by cerebrovascular occlusion and development of hemorrhage-prone collateral vessels. Approximately 10-12% of cases are familial, with a presumed low penetrance autosomal dominant pattern of inheritance. Diagnosis commonly occurs only after clinical presentation. The recent identification of the RNF213 founder mutation (p.R4810K) in the Asian population has made a significant contribution, but the etiology of this disease remains unclear. To further develop the variant landscape of MMD, we performed high-depth whole exome sequencing of 125 unrelated, predominantly nonfamilial, ethnically diverse MMD patients in parallel with 125 internally sequenced, matched controls using the same exome and analysis platform. Three subpopulations were established: Asian, Caucasian, and non-RNF213 founder mutation cases. We provided additional support for the previously observed RNF213 founder mutation (p.R4810K) in Asian cases (P = 6.01×10(-5)) that was enriched among East Asians compared to Southeast Asian and Pacific Islander cases (P = 9.52×10(-4)) and was absent in all Caucasian cases. The most enriched variant in Caucasian (P = 7.93×10(-4)) and non-RNF213 founder mutation (P = 1.51×10(-3)) cases was ZXDC (p.P562L), a gene involved in MHC Class II activation. Collapsing variant methodology ranked OBSCN, a gene involved in myofibrillogenesis, as most enriched in Caucasian (P = 1.07×10(-4)) and non-RNF213 founder mutation cases (P = 5.31×10(-5)). These findings further support the East Asian origins of the RNF213 (p.R4810K) variant and more fully describe the genetic landscape of multiethnic MMD, revealing novel, alternative candidate variants and genes that may be important in MMD etiology and diagnosis.
authors.affiliation: Department of Neurosurgery and Stanford Stroke Center, Stanford University, Stanford, California 94305.
authors.forename: Lorelei D
authors.initials: LD
authors.lastname: Shoemaker
authors.affiliation: Personalis Inc., Menlo Park, California 94025.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clark
authors.affiliation: Personalis Inc., Menlo Park, California 94025.
authors.forename: Anil
authors.initials: A
authors.lastname: Patwardhan
authors.affiliation: Personalis Inc., Menlo Park, California 94025.
authors.forename: Gemma
authors.initials: G
authors.lastname: Chandratillake
authors.affiliation: Personalis Inc., Menlo Park, California 94025.
authors.forename: Sarah
authors.initials: S
authors.lastname: Garcia
authors.affiliation: Personalis Inc., Menlo Park, California 94025.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Stanford Medical School, Stanford University, Stanford, California 94305.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Morgan
authors.affiliation: Personalis Inc., Menlo Park, California 94025.
authors.forename: Nan
authors.initials: N
authors.lastname: Leng
authors.affiliation: Personalis Inc., Menlo Park, California 94025.
authors.forename: Scott
authors.initials: S
authors.lastname: Kirk
authors.affiliation: Personalis Inc., Menlo Park, California 94025.
authors.forename: Richard
authors.initials: R
authors.lastname: Chen
authors.affiliation: Centre for Neuroscience Studies and the Department of Surgery, Queen's University, Kingston, Ontario, K7L 3N6.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Cook
authors.affiliation: Department of Genetics, Stanford University, Stanford, California 94305.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Department of Neurosurgery and Stanford Stroke Center, Stanford University, Stanford, California 94305 gsteinberg@stanford.edu.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Steinberg
mesh_terms: D000251:Adenosine Triphosphatases; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D005006:Ethnicity / Q000235:genetics*; D059472:Exome; D005260:Female; D018703:Founder Effect; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009072:Moyamoya Disease / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D016366:Open Reading Frames; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases
keywords: OBSCN; RNF213; ZXDC; cerebrovascular disease; hemorrhage