Whole-exome sequencing reveals the genetic causes and modifiers of moyamoya syndrome

Area of Science:

• Genetics
• Neurology
• Vascular Biology

Background:

• Moyamoya syndrome (MMS) is characterized by moyamoya vasculopathy secondary to various genetic disorders.
• Emerging evidence suggests MMS arises from a combination of genetic modifiers and causative mutations of primary genetic conditions.

Purpose of the Study:

• To investigate the genetic underpinnings of moyamoya syndrome (MMS) in patients with diverse genetic disorders.
• To identify potential genetic modifiers and causative variants contributing to MMS susceptibility.

Main Methods:

• Whole-exome sequencing (WES) was performed on 13 patients diagnosed with moyamoya syndrome (MMS) and various underlying genetic disorders.
• Genetic diagnoses included neurofibromatosis type 1, Down syndrome, multisystemic smooth muscle dysfunction syndrome, Noonan syndrome, and alpha thalassemia.
• Comparative analysis was conducted with the 1000 Genomes Project database.

Main Results:

• WES successfully identified genetic diagnoses for all 13 patients.
• Previously reported modifier genes (RNF213, MRVI1) were confirmed in specific cases.
• Rare hypomorphic variants in primary disorder genes (e.g., Alagille syndrome, Rasopathies) and pulmonary arterial hypertension (PAH) genes (e.g., ABCC8, BMPR2) were found to confer MMS susceptibility.
• Significant enrichment of rare variants in MMS and PAH genes was observed in Japanese MMS patients compared to controls.

Conclusions:

• Genetic factors, including rare variants in causative genes of primary disorders and potential modifier genes (e.g., PAH-associated genes), play a crucial role in moyamoya syndrome (MMS) development.
• These findings highlight novel diagnostic markers and potential therapeutic targets for MMS and moyamoya disease of unknown etiology.