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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
RNF213 rare variants in an ethnically diverse population with Moyamoya disease
Alana C Cecchi1, Dongchuan Guo1, Zhao Ren1
1From the Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center, Houston (A.C.C., D.G., Z.R., K.F., E.S.R., H.P., D.M.M.); Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX (R.L.P.S.-C., S.M.L., G.T.W.); Department of Genome Sciences (J.S., M.J.B., D.A.N.) and Department of Pediatrics (M.J.B.), University of Washington, Seattle; Department of Neurosurgery, Stanford University, CA (G.K.S.); and Clinical Innovation and Research Institute, Memorial Hermann Hospital, Houston, TX (J.C.G.).
Background And Purpose:
Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring Finger 213 gene (RNF213), altering arginine at position 4810 (p.R4810K), is associated with MMD in Asian populations. However, there are a lack of data on the role of RNF213 in patients with MMD of additional ethnicities and diasporic Asian populations. We investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States.
Methods:
We initially sequenced RNF213 exons 43, 44, and 45 (encoding the eponymous RING finger domain) and exon 60 (encoding p.R4810K) in 86 ethnically diverse patients with MMD. Comprehensive exome sequencing data from 24 additional patients with MMD was then analyzed to identify RNF213 variants globally. Segregation of variants with MMD and other vascular diseases was assessed in families.
Results:
RNF213 p.R4810K was identified in 56% (9/16) of patients with MMD of Asian descent and not in 94 patients of non-Asian descent. 3.6% (4/110) of patients had variants in the exons encoding the RING finger domain. Seven additional variants were identified in 29% (7/24) of patients with MMD who underwent exome sequencing. Segregation analysis supported an association with MMD for 2 variants and a lack of association with disease for 1 variant.
Conclusions:
These results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the United States to MMD.
Insights
Ring Finger 213 (RNF213) gene alterations predispose diverse ethnicities to Moyamoya disease (MMD). The p.R4810K variant specifically increases MMD risk in Asian populations within the United States.
Area of Science:
- Genetics
- Neurology
- Vascular Biology
Background:
- Moyamoya disease (MMD) is a rare cerebrovascular condition characterized by internal carotid artery occlusion.
- A known genetic link exists between the Ring Finger 213 (RNF213) gene variant (p.R4810K) and MMD, primarily observed in Asian populations.
- Limited data exists on RNF213's role in MMD across diverse ethnicities and diasporic Asian communities.
Purpose of the Study:
- To investigate the contribution of RNF213 gene alterations to Moyamoya disease (MMD) in a diverse, US-based population.
- To determine if RNF213 variants, including p.R4810K, are associated with MMD in non-Asian individuals.
- To explore the genetic landscape of MMD in ethnically varied patient cohorts.
Main Methods:
- Sequencing of key RNF213 exons (43, 44, 45, 60) in 86 ethnically diverse MMD patients.
- Analysis of comprehensive exome sequencing data from 24 additional MMD patients to identify RNF213 variants globally.
- Family-based segregation analysis to assess the association of identified variants with MMD and other vascular diseases.
Main Results:
- The RNF213 p.R4810K variant was found in 56% of Asian MMD patients but not in non-Asian patients.
- Variants within the RNF213 RING finger domain were identified in 3.6% of patients.
- Seven additional RNF213 variants were found in 29% of MMD patients undergoing exome sequencing, with segregation analysis supporting disease association for two.
Conclusions:
- RNF213 alterations are confirmed genetic predisposing factors for Moyamoya disease across diverse ethnicities.
- The RNF213 p.R4810K variant specifically predisposes individuals of Asian descent in the United States to MMD.
- Genetic analysis of RNF213 is crucial for understanding MMD in varied populations.
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