Identification and genotype-phenotype correlation of RNF213 p.R4810K and non- p.R4810K variants in Moyamoya disease in an Indian cohort.
Moyamoya disease is known to be associated with the Ring Finger 213 gene variant (RNF213 p.R4810K) in East Asians; however, it remains less studied in South Asians. This study aims to identify the RNF213 p.R4810K and non- p.R4810K variants and to investigate their phenotypic correlation in an Indian cohort of Moyamoya patients.
The study prospectively enrolled 100 patients with unilateral or bilateral Moyamoya disease (June 2023 to June 2024). Whole exome sequencing was performed to identify all the RNF213 exonic variants. The patients were grouped based on the single-nucleotide variants detected (RNF213 p.R4810K and non- p.R4810K variants) and their pathogenicity. The RNF213 p.R4810K variants were further categorized as homozygous and heterozygous. The demographic, clinical, and angiographic characteristics were collected. Statistical correlations of RNF213 polymorphisms with phenotypic features were assessed by Kruskall-Wallis tests and Fisher's Exact tests.
Seventy-four (74%) patients carried no RNF213 variants, while 26 (26%) carried RNF213 variants. The founder variant p.R4810K was detected in 9 (9%) patients, and non- p.R4810K variants in 19 (19%) patients. Five missense variants were reported as novel variants (p.Gln681Glu, p.Pro2875Ser, p.Leu4117Pro, p.Gln4029Arg, p.Asp4003Val). Among these, p.Leu4117Pro and p.Asp4003Val, located within the RING domain, were predicted to destabilize the protein structure. The genotype-phenotype correlation showed that the domicile state (p = 0.006), family history of Moyamoya disease (p = 0.001), and periventricular anastomosis (p = 0.026) were significantly different among patients with p.R4810K and non- p.R4810K variants than those without. There was no significant difference observed in clinical presentation or severity of the disease between homozygous and heterozygous carriers.
The study confirmed that both RNF213 p.R4810K and non- p.R4810K variants increase the risk of Moyamoya disease with variable phenotypic expression. Further functional studies in a large cohort would help in delineating the role of these variants in disease pathophysiology as well as in better genotype- phenotype correlations.
The study prospectively enrolled 100 patients with unilateral or bilateral Moyamoya disease (June 2023 to June 2024). Whole exome sequencing was performed to identify all the RNF213 exonic variants. The patients were grouped based on the single-nucleotide variants detected (RNF213 p.R4810K and non- p.R4810K variants) and their pathogenicity. The RNF213 p.R4810K variants were further categorized as homozygous and heterozygous. The demographic, clinical, and angiographic characteristics were collected. Statistical correlations of RNF213 polymorphisms with phenotypic features were assessed by Kruskall-Wallis tests and Fisher's Exact tests.
Seventy-four (74%) patients carried no RNF213 variants, while 26 (26%) carried RNF213 variants. The founder variant p.R4810K was detected in 9 (9%) patients, and non- p.R4810K variants in 19 (19%) patients. Five missense variants were reported as novel variants (p.Gln681Glu, p.Pro2875Ser, p.Leu4117Pro, p.Gln4029Arg, p.Asp4003Val). Among these, p.Leu4117Pro and p.Asp4003Val, located within the RING domain, were predicted to destabilize the protein structure. The genotype-phenotype correlation showed that the domicile state (p = 0.006), family history of Moyamoya disease (p = 0.001), and periventricular anastomosis (p = 0.026) were significantly different among patients with p.R4810K and non- p.R4810K variants than those without. There was no significant difference observed in clinical presentation or severity of the disease between homozygous and heterozygous carriers.
The study confirmed that both RNF213 p.R4810K and non- p.R4810K variants increase the risk of Moyamoya disease with variable phenotypic expression. Further functional studies in a large cohort would help in delineating the role of these variants in disease pathophysiology as well as in better genotype- phenotype correlations.
Authors
Sylaja Sylaja, Paul Paul, Madhusoodanan Madhusoodanan, Kumar Kumar, Nair Nair, Sarma Sarma, Fasaludeen Fasaludeen, Kumar Kumar, Jayadevan Jayadevan, Pachat Pachat, Sreedharan Sreedharan, Sudhir Sudhir, Muneeb Hamza Muneeb Hamza, Anjana Madhu Anjana Madhu, Banerjee Banerjee
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