RT Journal Article
SR Electronic
T1 Xq28 copy number gain causing moyamoya disease and a novel moyamoya syndrome
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 339
OP 346
DO 10.1136/jmedgenet-2019-106525
VO 57
IS 5
A1 Chaker Aloui
A1 Stéphanie Guey
A1 Eva Pipiras
A1 Manoelle Kossorotoff
A1 Sophie Guéden
A1 Michaelle Corpechot
A1 Pierre Bessou
A1 Jean-Michel Pedespan
A1 Marie Husson
A1 Dominique Hervé
A1 Florence Riant
A1 Markus Kraemer
A1 Julie Steffann
A1 Olivier Quenez
A1 Elisabeth Tournier-Lasserve
YR 2020
UL http://jmg.bmj.com/content/57/5/339.abstract
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.