Abstract DP174: Genetic Architecture of Moyamoya Disease (MMD) And Idiopathic Intracranial Major Artery Stenosis/Occlusion (ICASO) In India

Background: Our understanding of the genetic architecture of moyamoya disease (MMD) and idiopathic intracranial major artery stenosis/occlusion (ICASO) has been predominantly based on the East Asian population. There is scarce data on MMD/ICASO genetics in the South Asian population. We aimed to explore the genetics of MMD and ICASO in the Indian population by identifying population-specific variations that are unique to the Indian population, previously unknown dual pathogenic hits, and probably new genes which were never before linked to these disorders in our first unified large-scale genetic profile in India. Methods: We enrolled patients who met the criteria for both MMD and ICASO from our stroke registry. Whole exome sequencing (WES) was performed on all participants; a few cases additionally had whole genome sequencing (WGS) for a more comprehensive genetic map. Identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria, and virtual diagnostic panels were applied to the exome data. Sanger confirmation, family-based (trio) testing, gene burden testing, and a population-wide GWAS are planned as part of this ongoing study. Results: To date, we recruited 71 MMD, 57 ICASO, 62 with early-onset stroke, which also includes arterial dissection, and 66 healthy controls. In typical MMD cases, RNF213 variants appeared in 20% of cases, including the well-known p.Arg4810Lys mutation and novel missense and splice-site (c.10424-2A>C) changes. Additionally, MTHFR, SMARCAL1, ABCC6 (pathogenic), KDR, PCNT, COL4A2, and novel ANO1 association were identified, all showing typical MMD clinical and imaging characteristics. In ICASO cases, RNF213 variants were present in 8.5%, with additional NOTCH3, NOS3, KRIT1, and SLC1A3. Most remarkably, we have identified novel dual-hit combinations (RNF213–TGFBR1, RNF213–SERPIND1) in ICASO cases. The genetic patterns in both MMD and ICASO were notably different from those in stroke and healthy individuals, with multiple mutations unique to Indian patients. Conclusions: Our Indian genomic study uncovers the molecular architecture of MMD and ICASO in the South Asian population, which should pave the way for larger multicentre studies in South Asia.