Xq28 copy number gain causing moyamoya disease and a novel moyamoya syndrome.

J Med Genet 2020 05 10;57(5):339-346. Epub 2020 Jan 10.

Université de Paris, NeuroDiderot, Inserm UMR1141, Paris, France

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.

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2019-106525DOI Listing
May 2020

Publication Analysis

Top Keywords

array data
8
moyamoya disease
8
snp array
8
xq28 cnv
8
rare novo
8
novo cnvs
8
causing moyamoya
8
additional families
8
copy number
8
moyamoya
7
novo
5
database control
4
control genomic
4
genomic variants
4
variants gnomad
4
standard database
4
gold standard
4
curated gold
4
coactivator typical
4
notch coactivator
4

Similar Publications