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

Abstract

Purpose: 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.

Methods: Exome sequencing from 39 trios were analyzed.

Results: 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.

Conclusion: 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.

Keywords: chromatin remodeling; developmental disorders; exome sequencing; moyamoya angiopathy.

Fig. 1. Schematic representation of domains of the proteins encoded by CHD4, CNOT3, and SETD5 and the location of the rare variants identified in individuals with either moyamoya angiopathy (MMA) or developmental disorders.

Above the protein schematics are the location of rare de novo variants (red) and variants (black) identified in singleton cases in the MMA cohort. Below the protein schematics are variants identified in children with intellectual disability, congenital heart defects, or developmental disorders (blue).^, The red variant in the CHD4 schematic was identified in three unrelated patients, including the patient described with intellectual disability and moyamoya disease (CHD4: NP_001264.2, CNOT3: NP_055331.1, SETD5: NP_001073986.1). ATP adenosine triphosphate.