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

Abstract

BackgroundThe molecular anomalies causing moyamoya disease (MMD) and moyamoya syndromes (MMS) are unknown in most patients.ObjectiveThis study aimed to identify de novo candidate copy number variants (CNVs) in patients with moyamoya.MethodsRare 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.ResultsTwo 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.ConclusionThe 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.

Livedo racemosa in neurological diseases: an update on the differential diagnoses

“…3) [38]. It has a higher incidence in Japan and Korea, probably due to founder mutations [39][40][41][42]. Histopathological studies have shown that pathophysiological pathways of European and Asian MA seem identical despite different genetic predispositions [43].…”

Epigenome-Wide Association Study Reveals Differential Methylation Sites and Association of Gene Expression Regulation with Ischemic Moyamoya Disease in Adults

“…( 8 ). Some studies have indicated the importance of investigating the effect of pathways of interest on the occurrence and development of MMD ( 14 – 16 ). However, information regarding the significantly different methylation sites in adult ischemic MMD remains scarce.…”

Physiological and pathophysiological mechanisms of the molecular and cellular biology of angiogenesis and inflammation in moyamoya angiopathy and related vascular diseases

“…The research group has demonstrated a new Xq28 CNV gain in both MMA and a novel MMS related to pulmonary vein stenosis, pulmonary hypertension, and other distinct systemic venous anomalies. These data may be relevant for clinical care and genetic counseling (319). MMA patients may present with a significantly increased rate of persistent carotidvertebrobasilar anastomoses compared to controls (320), and may be 26 times more likely to suffer from Down's syndrome (321, 322).…”