In Reply

Abstract

In Reply: We thank Dr Kapoor for his interest in our article on sex differences in clinical presentation and treatment outcomes in moyamoya disease (MMD), and share in his enthusiasm for research on genetic factors that underlie the susceptibility and clinical course of MMD. Several lines of evidence have long supported an underlying genetic susceptibility to MMD as reviewed by Achrol et al.1 Familial occurrence in as many as 15% of individuals with MMD, concordance rates as high as 80% in monozygotic twins with MMD, and apparent autosomal dominant transmission with incomplete penetrance in Japanese families with MMD, were all previously described. Further work suggested the autosomal dominant transmission of MMD in Japanese families mapped to chromosome 17q25.2 Chromosome 17 was already of interest given the association between MMD and neurofibromatosis Type 1, for which the causative gene (NF1) had been identified on chromosome 17q11.2. Using microsatellite markers and an affected-member-only approach in Japanese families, a candidate locus was suggested at 17q25.3 A separate analysis in 15 extended Japanese families using genome-wide parametric linkage analysis also identified a candidate locus at 17q25.3.2 Collectively, these data provided compelling evidence that a pathogenic gene associated with familial MMD in Japanese patients might be found on chromosome 17q25. The recent Kamada et al4 genome-wide association follow-up analysis of 785,720 SNPs demonstrated that SNPs in the 17q25-ter region reached a significance of P < 10−8. Their locus-specific association study of 384 SNP markers within the chromosome 17q25-ter region found that SNP markers most highly associated with MMD fell entirely within the RNF213 locus. Almost simultaneously, Liu et al5 discovered an RNF213 variant using exome analysis of 8 index cases of familial MMD. Additional single-gene mutations have also been closely associated with MMD. Mutations in smooth muscle alpha actin (ACTA2) can cause MMD, as well as premature coronary artery disease and thoracic aortic disease.6 Recently Xq28 deletions removing MTCP1/MTCP1NB and BRCC3 have been shown to cause a type of X-linked familial moyamoya syndrome.7 While these results mark a major genetic advance toward understanding the underlying pathogenesis of MMD and elucidating potential pathways for therapeutic intervention, they should be interpreted with certain caveats in mind. For example, it could not be demonstrated that variants of RNF213 altered or impaired physiological function or mRNA levels and therefore it remains unclear how these variants could contribute to the development of MMD. Furthermore, it is unclear why the disease prevalence in this population (1 in 100 000) is lower than expected given the much higher minor allele frequency of 1%. Importantly, neither the p.R4859K mutation found by Kamada et al4 nor the p.R4810K mutation found by Liu et al5 were observed in any of the Caucasian patients and controls tested, suggesting the genetic background of MMD in Japanese populations may be distinct from that in Western populations, and that RNF213 may represent a founder mutation specific to these Japanese families. It should also be noted, even when limited to Japanese families, genetic linkage studies have reported varied results, with 5 different chromosomal regions of interest reported in the past: 3p24.2–p26, 6q25, 8q23, 12p12, and 17q25 (reviewed in Achrol et al1). Taken together with the fact that RNF213 minor allele frequency appears much more prevalent than disease prevalence and that the same variants present in Japanese patients were not found in Caucasian patients, these data suggest that much work remains to be done to elucidate the pathogenesis of MMD. We share in Dr Kapoor's enthusiasm for these recent major genetic advancements, and believe these results should serve to encourage further research on genetic factors that underlie the susceptibility and clinical course of MMD. Disclosure The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.