Background The molecular anomalies causing moyamoya disease (MMD) and moyamoya syndromes (MMS) are unknown in most patients.
Objective This study aimed to identify de novo candidate copy number variants (CNVs) in patients with moyamoya.
Methods Rare de novo CNVs screening was performed in 13 moyamoya angiopathy trios using whole exome sequencing (WES) reads depth data and whole genome high density SNP array data. WES and SNP array data from an additional cohort of 115 unrelated moyamoya probands were used to search for recurrence of these rare de novo CNVs.
Results Two de novo CNVs were identified in two unrelated probands by both methods and confirmed by qPCR. One of these CNVs, located on Xq28, was detected in two additional families. This interstitial Xq28 CNV gain is absent from curated gold standard database of control genomic variants and gnomAD databases. The critical region contains five genes, including MAMLD1, a major NOTCH coactivator. Typical MMD was observed in the two families with a duplication, whereas in the triplicated patients of the third family, a novel MMS associating moyamoya and various systemic venous anomalies was evidenced.
Conclusion The recurrence of this novel Xq28 CNV, its de novo occurrence in one patient and its familial segregation with the affected phenotype in two additional families strongly suggest that it is pathogenic. In addition to genetic counselling application, its association with pulmonary hypertension is of major importance for clinical care. These data also provide new insights into the genomic architecture of this emblematic, non-atherosclerotic, large vessel disease.
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SG and EP contributed equally.
Contributors CA, StG, ETL: study design. MKo, StG, PB, JMP, MH, SoG, DH, MKr: clinical and neuroimaging investigation and sample collection. MC, JS, EP, FR: experimental work and data interpretation. CA, EP, StG, OQ, ETL: exome and SNP array data analysis and interpretation. CA, StG, MKo, SoG, ETL: first draft of the manuscript. All authors read and approved the final manuscript. StG and EP are cosecond authors.
Funding This work was supported by Inserm. SG was a Fondation pour la Recherche Médicale fellowship recipient (FDM40678).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.