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The pleiotropy associated with de novo variants in CHD4 , CNOT3 , and SETD5 extends to moyamoya angiopathy

Published on Feb 1, 2020in Genetics in Medicine8.683
· DOI :10.1038/S41436-019-0639-2
Amélie Pinard2
Estimated H-index: 2
(University of Texas Health Science Center at Houston),
Stéphanie Guey5
Estimated H-index: 5
(Paris Diderot University)
+ 15 AuthorsDianna M. Milewicz58
Estimated H-index: 58
(University of Texas Health Science Center at Houston)
Abstract
Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger. Exome sequencing from 39 trios were analyzed. We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease. These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.
  • References (20)
  • Citations (2)
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References20
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Shortening and removal of the polyadenylate [poly(A)] tail of mRNA, a process called deadenylation, is a key step in mRNA decay that is mediated through the CCR4-NOT (carbon catabolite repression 4–negative on TATA-less) complex. In our investigation of the regulation of mRNA deadenylation in the heart, we found that this complex was required to prevent cell death. Conditional deletion of the CCR4-NOT complex components Cnot1 or Cnot3 resulted in the formation of autophagic vacuoles and cardiomy...
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ABSTRACT MicroRNAs are key regulators of angiogenesis, as illustrated by the vascular defects observed in miR-126-deficient animals. The miR-126 duplex gives rise to two mature microRNAs (miR-126-3p and -5p). The vascular defects in these mutant animals were attributed to the loss of miR-126-3p but the role of miR-126-5p during normal angiogenesis in vivo remains unknown. Here, we show that miR-126-5p is expressed in endothelial cells but also by retinal ganglion cells (RGCs) of the mouse postna...
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SET-domain containing proteins play a vital role in regulating gene expression during development through modifications in chromatin structure. Here we show that SET domain containing 5 ( Setd5 ) is divergently transcribed with Gt(ROSA26)Sor , is necessary for mammalian development, and interacts with the PAF1 co-transcriptional complex and other proteins. Setd5 -deficient embryos exhibit severe defects in neural tube formation, somitogenesis, and cardiac development, have aberrant vasculogenesi...
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#1Karin Weiss (NIH: National Institutes of Health)H-Index: 6
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Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2β, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developm...
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#1Dominique Hervé (French Institute of Health and Medical Research)H-Index: 22
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Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal “moyamoya” vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-reces...
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#1Ruben RochaH-Index: 5
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Cited By2
Newest
#1Oliver Sander (HHU: University of Düsseldorf)H-Index: 14
#2Jan Claudius Schwitalla (RUB: Ruhr University Bochum)H-Index: 5
Last. Markus Kraemer (HHU: University of Düsseldorf)H-Index: 4
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OBJECTIVE: In Europe, MMA is a very rare non-inflammatory vasculopathy. MMA is an important differential diagnosis of cerebral vasculitis. Systemic manifestations, such as livedo racemosa or renal artery stenosis, associated with Moyamoya variants suggest the involvement also of non-cerebral vessels. Hypothetically, capillary microscopy could be a promising non-invasive screening method to visualize microcirculation, for example prior to cerebral angiography. METHODS: Standardized capillary micr...
Source
#1Chaker Aloui (University of Paris)H-Index: 7
#1Chaker Aloui (University of Paris)
Last. Elisabeth Tournier-Lasserve (University of Paris)H-Index: 51
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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...
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