PT  - JOURNAL ARTICLE
AU  - Chaker Aloui
AU  - Stéphanie Guey
AU  - Eva Pipiras
AU  - Manoelle Kossorotoff
AU  - Sophie Guéden
AU  - Michaelle Corpechot
AU  - Pierre Bessou
AU  - Jean-Michel Pedespan
AU  - Marie Husson
AU  - Dominique Hervé
AU  - Florence Riant
AU  - Markus Kraemer
AU  - Julie Steffann
AU  - Olivier Quenez
AU  - Elisabeth Tournier-Lasserve
TI  - Xq28 copy number gain causing moyamoya disease and a novel moyamoya syndrome
AID  - 10.1136/jmedgenet-2019-106525
DP  - 2020 May 01
TA  - Journal of Medical Genetics
PG  - 339--346
VI  - 57
IP  - 5
4099  - http://jmg.bmj.com/content/57/5/339.short
4100  - http://jmg.bmj.com/content/57/5/339.full
SO  - J Med Genet2020 May 01; 57
AB  - 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.