RNF213 variant in a patient with Legius syndrome associated with moyamoya syndrome.
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ABSTRACT:
SUBMITTER: Romanisio G
PROVIDER: S-EPMC8222830 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Introducción. La enfermedad de moyamoya es una enfermedad estenooclusiva progresiva de las principales arterias intracraneales. Los individuos afectados corren el riesgo de sufrir un accidente cerebrovascular hemorrágico o isquémico intracraneal, deterioro cognitivo y retrasos en el desarrollo. Se han identificado varios genes de susceptibilidad. La variante p.R4810K en el gen RNF213 se ha identificado en el 95% de los pacientes con enfermedad de moyamoya familiar. Caso clínico. Presentamos el caso de una adolescente de 15 años que se presentó con quejas principales de disgrafía y falta de coordinación en la mano derecha con dos meses de evolución. La resonancia magnética cerebral reveló varias lesiones isquémicas con diferentes ritmos de evolución y la angiorresonancia magnética mostró múltiples estenosis suboclusivas. En el estudio de las secuencias de las regiones codificantes y de las regiones intrónicas flanqueantes (±8 pb) del gen RNF213, se detectó la variante c.12185G>A, p.(Arg4062Gln) en heterocigosidad en el gen RNF213. Este resultado indica que la paciente es heterocigota para la variante c.12185G>A, p.(Arg4062Gln) en el gen RNF213. La variante detectada ya ha sido descrita en la bibliografía como una variante fundadora en la población asiática, asociada a síndrome de moyamoya. Esta variante está descrita en ClinVar como una variante de significado clínico desconocido. Además, no está descrita en las bases de datos poblacionales (dbSNP, ESP y gnomAD). Conclusión. Hasta donde sabemos, la variante p.(Arg4062Gln) se ha notificado en tres pacientes japoneses con enfermedad de moyamoya y en uno europeo. Por lo tanto, nuestro paciente fue el segundo europeo con enfermedad de moyamoya con esta variante identificada.
| S-EPMC10364028 | biostudies-literature
Project description:IntroductionRecent studies have suggested associations between RNF213 variants and the formation of periventricular anastomosis among patients with moyamoya disease, leading to early onset of cerebral hemorrhage and rebleeding.Case descriptionWe report herein the case of a boy with Down syndrome and moyamoya syndrome. Exome sequencing identified a heterozygous RNF213 R4810K variant. After ischemic stroke occurred at 9 years old, indirect surgical revascularization was performed for the left cerebral hemisphere and improved ischemic symptoms and cerebral hypoperfusion, while the left choroidal anastomosis remained. At 13 years old, he presented with left thalamic hemorrhage attributed to the anterior choroidal artery, with rebleeding observed four days after the initial hemorrhage under strict blood pressure control. The patient was discharged without neurological deficits 20 days after the hemorrhagic stroke.ConclusionPresence of an RNF213 variant and choroidal anastomosis may represent risk factors for cerebral hemorrhage in patients with Down syndrome and moyamoya syndrome, as well as in patients with moyamoya disease.
| S-EPMC10652563 | biostudies-literature
Project description:BackgroundMoyamoya disease (MMD) is a progressive steno-occlusive vasculopathy that involves large intracranial arteries accompanied by abnormal collateral vessels. Recently, RNF213 was identified as a susceptibility gene for MMD and p.Arg4810Lys (rs112735431) is the most common variant in East Asian MMD patients. Interestingly, many studies have reported that a certain proportion of the general population in Japan, Korea, and China also has this variant. In this study, we investigated the frequency of this variant and estimated an odds ratio of MMD using two different Korean populations.MethodsA total of 1,516 anonymous DNA samples, 799 from an umbilical cord blood bank and 717 from routine health-checked adults, were genotyped using targeted Sanger sequencing.ResultsThe p.Arg4810Lys variant was detected at genotype frequencies of 2.25% (18/799; 95% confidence interval (CI), 1.43-3.53%) in cord blood samples and 2.65% (19/717; 95% CI, 1.70-4.10%) in adult samples, respectively. This variant showed a strong association with MMD (P < 0.001), giving an odds ratio of 162.7 (95% CI, 65.5-403.9) and 137.8 (95% CI, 55.8-339.9) based on the cord blood and adults samples, respectively.ConclusionsThese results confirm that the RNF213 p.Arg4810Lys variant is not uncommon in the general Korean population and provide reference data for the association of this variant and MMD.
| S-EPMC4654917 | biostudies-literature
Project description:Segmental infantile hemangiomas (IH) can be associated with congenital anomalies in a regional distribution. PHACE refers to large cervicofacial segmental IH in association with congenital anomalies of the aortic arch and medium-sized arteries of the head and neck, as well as structural anomalies of the posterior fossa and eye. A subset of PHACE patients have arterial anomalies that progress to moyamoya vasculopathy (MMV). MMV is defined as stenosis of the supraclinoid segment of the internal carotid arteries and/or their major branches, with subsequent development of a compensatory collateral vessel network. We describe a patient with MMV and segmental IH on the back and lower body who meets diagnostic criteria for PHACE based on a posterior segment eye anomaly and cerebral arterial anomalies. Whole exome sequencing demonstrated two inherited heterozygous variants in RNF213. Variants in RNF213 are associated with increased susceptibility to MMV. Our findings suggest that RNF213 variants may play a role in the development of MMV in patients with hemangioma syndromes associated with congenital cerebral arterial anomalies.
| S-EPMC5815368 | biostudies-literature
Project description:BackgroundThe genetic architecture of coronary artery disease has not been fully elucidated, especially in Asian countries. Moyamoya disease is a progressive cerebrovascular disease that is reported to be complicated by coronary artery disease. Because most Japanese patients with moyamoya disease carry the p.R4810K variant of the ring finger 213 gene (RNF213), this may also be a risk factor for coronary artery disease; however, this possibility has never been tested.Methods and resultsWe genotyped the RNF213 p.R4810K variant in 956 coronary artery disease patients and 716 controls and tested the association between p.R4810K and coronary artery disease. We also validated the association in an independent population of 311 coronary artery disease patients and 494 controls. In the replication study, the p.R4810K genotypes were imputed from genome-wide genotyping data based on the 1000 Genomes Project. We used multivariate logistic regression analyses to adjust for well-known risk factors such as dyslipidemia and smoking habits. In the primary study population, the frequency of the minor variant allele was significantly higher in patients with coronary artery disease than in controls (2.04% vs. 0.98%), with an odds ratio of 2.11 (p = 0.017). Under a dominant model, after adjustment for risk factors, the association remained significant, with an odds ratio of 2.90 (95% confidence interval: 1.37-6.61; p = 0.005). In the replication study, the association was significant after adjustment for age and sex (odds ratio = 4.99; 95% confidence interval: 1.16-21.53; p = 0.031), although it did not reach statistical significance when further adjusted for risk factors (odds ratio = 3.82; 95% confidence interval: 0.87-16.77; p = 0.076).ConclusionsThe RNF213 p.R4810K variant appears to be significantly associated with coronary artery disease in the Japanese population.
| S-EPMC5393571 | biostudies-literature
Project description:Background Early-stage unilateral moyamoya disease (MMD) is difficult to discriminate from isolated intracranial atherosclerotic stenosis, and identification of contralateral progression may aid in the diagnosis of MMD. The RNF213 (ring finger protein 213) R4810K variant is a strong genetic susceptibility factor for MMD; however, the role of contralateral progression in unilateral MMD is unknown. Methods and Results Patients who had undergone RNF213 R4810K genotyping with suspected unilateral MMD between January 2017 and August 2021 from 2 tertiary university hospitals were retrospectively reviewed. We compared the clinical features and radiographic outcomes of patients with and without this variant. The risk factors of contralateral progression in patients with suspected unilateral MMD were evaluated. The RNF213 R4810K variant was observed in 72 of 123 patients with suspected unilateral MMD, all of which were heterozygous. The allele frequency of the R4810K variant was significantly higher in the suspected unilateral MMD group compared with the historical control group (29.3% versus 1.2%; P<0.0001). Family history of MMD was significantly more common in patients with the variant than in those without (17% versus 4%; P=0.003). Eleven of 72 patients with the variant developed contralateral progression, whereas only 1 of 51 patients without the variant developed contralateral progression during a median follow-up period of 28 months (log-rank test; P=0.03). The presence of the RNF213 R4810K variant significantly correlated with contralateral progression (adjusted odds ratio, 6.39 [95% CI, 1.11-36.63]; P=0.04). Conclusions Contralateral progression is more likely to occur in patients with suspected unilateral MMD with the RNF213 R4810K variant than in those without the variant. However, because our study used a small sample size, this finding should be carefully interpreted and requires further studies with more patients and longer follow-up periods.
| S-EPMC9375476 | biostudies-literature
Project description: Not available
| S-EPMC10250872 | biostudies-literature
Project description:Variants in RNF213 lead to susceptibility to moyamoya disease, a rare cerebral angiopathy characterized by bilateral stenosis of the internal carotid arteries and development of a compensatory collateral network. We describe a 3-month-old female with seizures, arterial narrowing involving the internal carotid and intracranial arteries and inferior abdominal aorta, and persistently elevated transaminases. Whole exome sequencing demonstrated a novel de novo variant in RNF213, securing a molecular diagnosis and directing appropriate intervention. This report underscores the role of whole exome sequencing in cases for which a complex and atypical presentation may mask diagnosis. Furthermore, the early and severe presentation in our patient, in conjunction with a novel de novo RNF213 variant, suggests that specific variants in RNF213 may lead to a Mendelian form of disease rather than simply conferring susceptibility to multifactorial disease.
| S-EPMC4639746 | biostudies-literature
Project description:The cerebrovascular disorder moyamoya disease (MMD) was first described in 1957 in Japan, and is typically considered to be an Asian-specific disease. However, it is globally recognized as one of the major causes of childhood stroke. Although several monogenic diseases are known to be complicated by Moyamoya angiopathy, the ring finger protein 213 gene (RNF213) was identified as a susceptibility gene for MMD. RNF213 is unusual, because (1) it induces MMD with no other recognizable phenotypes, (2) the RNF213 p.R4810K variant is an Asian founder mutation common to Japanese, Korean and Chinese with carrier rates of 0.5-2% of the general population but a low penetrance, and (3) it encodes a relatively largest proteins with a dual AAA+ ATPase and E3 Ligase activities. In this review, we focus on the genetics and genetic epidemiology of RNF213, the pathology of RNF213 R4810K, and the molecular functions of RNF213, and also address the public health contributions to current unresolved issues of MMD. We also emphasize the importance of a more updated definition for MMD, of qualified cohort studies based on genetic epidemiology and an awareness of the ethical issues associated with genetic testing of carriers.
| S-EPMC4771639 | biostudies-literature
Project description:Ring-finger protein 213 (RNF213) encodes a protein of unknown function believed to play a role in cellular metabolism and angiogenesis. Gene variants are associated with susceptibility to moyamoya disease. Here, we describe two children with moyamoya disease who also demonstrated kidney disease, elevated aminotransferases, and recurrent skin lesions found by exome sequencing to have de novo missense variants in RNF213. These cases highlight the ability of RNF213 to cause Mendelian moyamoya disease in addition to acting as a genetic susceptibility locus. The cases also suggest a new, multi-organ RNF213-spectrum disease characterized by liver, skin, and kidney pathology in addition to severe moyamoya disease caused by heterozygous, de novo C-terminal RNF213 missense variants.
| S-EPMC8360119 | biostudies-literature