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. 2015 Nov 3;6(1):41-9.
doi: 10.1534/g3.115.020321.

Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing

Lorelei D Shoemaker  1 , Michael J Clark  2 , Anil Patwardhan  2 , Gemma Chandratillake  2 , Sarah Garcia  2 , Rong Chen  2 , Alexander A Morgan  3 , Nan Leng  2 , Scott Kirk  2 , Richard Chen  2 , Douglas J Cook  4 , Michael Snyder  5 , Gary K Steinberg  6
Affiliations

Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing

Lorelei D Shoemaker et al. G3 (Bethesda). .

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.

Keywords: OBSCN; RNF213; ZXDC; cerebrovascular disease; hemorrhage.

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Figures

Figure 1
Figure 1
Case-control workflow for variant discovery. There were 125 MMD cases individually matched based on ethnicity and sex to 125 subject samples drawn from the Personalis Controls Library. Samples were analyzed in a stepwise process of exome sequencing, variant alignment and detection, and variant annotation to obtain 1,448,255 variants across 250 samples (A). This sample set was subdivided to construct three case-control datasets based on ethnicity (East Asian/Southeast Asian/Pacific Islander; Caucasian) and on the lack of the RNF213 founder variant (B). In each of these case-control datasets, variants were filtered to include only those with adequate call quality and excluded those with >30% missing data across samples (C). These variant sets were used to create a list of enriched variants (P < 0.0001) for each case-control study assuming an additive model (D).
Figure 2
Figure 2
Comparison of nonsynonymous variants in RNF213 between MMD cases and controls in the East Asian/Southeast Asian/Pacific Islander population. The schematic on the left shows the location of individual variants within the RNF213 exons, with the founder mutation (p.R4810K) located in the bottom row (A). The MMD cases are grouped in (B) while the control cases are grouped in (C). The occurrence of individual variants (rows) within the RNF213 gene across individual samples (columns) is indicated by a black (homozygous for alternative allele), gray (heterozygous), or white (no alternative allele) color scheme. Rows are ordered top (3′ end) to bottom (5′ end) by chromosomal position of the SNP and are labeled with the associated amino acid change. Ethnicities are shown per sample with distinguishing colors in the top row and associated legend. All identified variants within the RNF213 gene are missense, including one (p.R4810G) that occurs in the same codon as the founder variant. *Previously published protein-coding RNF213 variant (Kamada et al. 2011; Liu et al. 2011; Miyatake et al. 2012; Wu et al. 2012).
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