Missense variants in the chromatin remodeler <i>CHD1</i> are associated with neurodevelopmental disability

Pilarowski, Genay; Vernon, Hilary J.; Applegate, Carolyn D.; Boukas, Leandros; Cho, Megan T.; Gurnett, Christina A.; Benke, Paul J.; Beaver, Erin; Heeley, Jennifer; Medne, Līvija; Krantz, Ian D.; Azage, Meron; Niyazov, Dmitriy; Henderson, Lindsay B.; Wentzensen, Ingrid M.; Baskin, Berivan; Sacoto, María J. Guillen; Bowman, Gregory D.; Björnsson, Hans T.

doi:10.1136/jmedgenet-2017-104759

Cited by 52 publications

(54 citation statements)

References 45 publications

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“…However, comparisons to the CHD4-related syndrome are currently limited because so far only five individuals with CHD4 mutations have been clinically characterized. Also interesting in this context is the fact that four of the six recently described patients with missense mutations in CHD1 have a diagnosis of speech apraxia 9 , a relatively rare condition. Although CHD1 does not function in the same protein complex as CHD3 and has different expression patterns 9 , there might be shared pathogenic mechanisms leading to speech problems in patients with mutations in these chromatin remodelers.…”

Section: Discussionmentioning

confidence: 99%

“…The Chromodomain Helicase DNA-binding (CHD) protein family is a key class of ATP-dependent chromatin remodeling proteins, which utilize energy derived from ATP hydrolysis to regulate chromatin structure, thereby modulating gene expression 1 , 2 . CHD proteins are crucial for developmental processes 1 , 3 , with various members implicated in major neurodevelopmental disorders including CHD2 in epileptic encephalopathy 4 , CHD7 in CHARGE syndrome 5 , CHD8 in autism 6 , 7 , and more recently CHD4 and CHD1 in neurodevelopmental syndromes 8 , 9 . Three CHD proteins (CHD3, CHD4, and CHD5) can exert their chromatin remodeling activity by forming the core ATPase subunit of the NuRD complex 1 , 10 – 12 .…”

Section: Introductionmentioning

confidence: 99%

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CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Blok¹,

Rousseau²,

Twist³

et al. 2018

Nat Commun

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Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Blok¹,

Rousseau²,

Twist³

et al. 2018

Nat Commun

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“…Similarly, there have been other recent descriptions of relatively isolated speech apraxia (Pilarowski et al . ). Thus, there are disorders that lead to disproportional problems with individual aspects of cognitive function.…”

Section: Discussionmentioning

confidence: 97%

Molecularly confirmed Kabuki (Niikawa‐Kuroki) syndrome patients demonstrate a specific cognitive profile with extensive visuospatial abnormalities

Harris

Mahone

Björnsson

2019

J intellect Disabil Res

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Background Kabuki (Niikawa-Kuroki) syndrome (KS) is caused by disease-causing variants in either of two components (KMT2D and KDM6A) of the histone methylation machinery. Nearly all individuals with KS have cognitive difficulties, and most have intellectual disability. Recent studies on a mouse model of KS suggest disruption of normal adult neurogenesis in the granule cell layer of the dentate gyrus of the hippocampus. These mutant mice also demonstrate hippocampal memory defects compared with littermates, but this phenotype is rescued postnatally with agents that target the epigenetic machinery. If these findings are relevant to humans with KS, we would expect significant and disproportionate disruption of visuospatial functioning in these individuals.Methods To test this hypothesis, we have compiled a battery to robustly explore visuospatial function. We prospectively recruited 22 patients with molecularly confirmed KS and 22 IQ-matched patients with intellectual disability. Results We observed significant deficiencies in visual motor, visual perception and visual motor memory in the KS group compared with the IQ-matched group on several measures. In contrast, language function appeared to be marginally better in the KS group compared with the IQ-matched group in a sentence comprehension task. Conclusions Together, our data suggest specific disruption of visuospatial function, likely linked to the dentate gyrus, in individuals with KS and provide the groundwork for a novel and specific outcome measure for a clinical trial in a KS population.

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“…Perhaps not surprisingly for a family of genes with such important and conserved cellular functions, genetic perturbation of the CHDs has been linked to a number of human disorders. The first human CHD gene linked to disease was CHD7 , found to be causative of CHARGE syndrome (MIM 214800) [ 7 ], with variants in CHD1 [ 8 ], CHD2 [ 9 ], CHD4 [ 10 ], and CHD8 [ 11 ], identified as causes of Pilarowski-Bjornsson syndrome (MIM 617682), Epileptic encephalopathy (MIM 615369), Sifrim-Hitz-Weiss syndrome (MIM 617159), and autism spectrum disorders (MIM 615032), respectively. In 2018 CHD3 emerged as the latest CHD gene to be associated with a human syndrome, with variants in CHD3 identified in 35 patients with a novel neurodevelopmental disorder, Snijders Blok-Campeau syndrome (MIM 618205) [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome

et al. 2020

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There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 ( CHD3 ), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.

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Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability

Cited by 52 publications

References 45 publications

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Molecularly confirmed Kabuki (Niikawa‐Kuroki) syndrome patients demonstrate a specific cognitive profile with extensive visuospatial abnormalities

A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome

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