BRCC3 -Associated Syndromic Moyamoya Angiopathy Diagnosed Through Clinical RNA Sequencing

Moyamoya angiopathy is a cerebral vasculopathy causing progressive stenosis of the internal carotid arteries and the compensatory development of collateral blood vessels, leading to brain ischemia and an increased risk of cerebral haemorrhage. Although multiple non-genetic causes have been associated with moyamoya syndrome, it can also be associated with rare genetic syndromes. Moyamoya Disease 4, characterised by a short stature, hypergonadotropic hypogonadism and facial dysmorphism (MYMY4, OMIM #300845), also referred to as BRCC3-associated moyamoya syndrome, has so far been described in 11 individuals. Here, we describe a 23-year-old male presenting with moyamoya syndrome, global developmental delay and intellectual disability, epilepsy, short stature and dysmorphic features, who after > 17 years of uninformative diagnostics was diagnosed with BRCC3-associated moyamoya syndrome after clinical RNA-seq. Transcriptome analysis showed reduced expression of the likely disease-causing gene BRCC3 in patient-derived fibroblasts, which was subsequently found to be caused by a ~ 26 kb Xq28 deletion. We furthermore review all reported cases of BRCC3-associated moyamoya syndrome, further delineating this clinical entity.