Dataset Information

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature.

ABSTRACT:

Background

We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern.

Results

Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject.

Conclusions

We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis.

SUBMITTER: Ciolfi A

PROVIDER: S-EPMC6947958 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature.

Ciolfi Andrea A Aref-Eshghi Erfan E Pizzi Simone S Pedace Lucia L Miele Evelina E Kerkhof Jennifer J Flex Elisabetta E Martinelli Simone S Radio Francesca Clementina FC Ruivenkamp Claudia A L CAL Santen Gijs W E GWE Bijlsma Emilia E Barge-Schaapveld Daniela D Ounap Katrin K Siu Victoria Mok VM Kooy R Frank RF Dallapiccola Bruno B Sadikovic Bekim B Tartaglia Marco M

Clinical epigenetics 20200107 1

<h4>Background</h4>We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern.<h4>Results</h4>Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying thi ...[more]

PMID: 31910894

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Project description:Rahman syndrome (RMNS) is a rare genetic disorder characterized by mild to severe intellectual disability, hypotonia, anxiety, autism spectrum disorder, vision problems, bone abnormalities, and dysmorphic facies. De novo heterozygous mutations in H1-4 encoding the linker histone H1.4 are found in individuals with RMNS; however, the underlying mechanisms causing significantly impaired neurodevelopment are not understood. So far, all neurodevelopmental associated mutations in H1-4 are small insertions or deletions that create a shared frameshift, resulting in a H1.4 protein that is both truncated and possessing an abnormal C-terminus frameshifted tail (H1.4 CFT). To expand understanding of mutations and phenotypes associated with mutant H1-4, we identified additional and new DNA variants at both the C- and N-terminus of H1.4. The clinical features of mutations identified at the C-terminus are consistent with other reports that strengthen the support of pathogenicity of H1.4 CFT. However, the pathogenicity of disrupting variants at the N-terminus could not be determined. To understand how H1.4 CFT may disrupt brain function, we exogenously expressed wildtype or H1.4 CFT protein in primary rat hippocampal neurons and assessed neuronal structure and function. Genome-wide transcriptome analysis revealed ~400 genes altered specifically in the presence of H1.4 CFT. Neuronal genes downregulated by H1.4 CFT were enriched for functional categories involved in synaptic communication and neuropeptide signaling. Neurons expressing H1.4 CFT showed reduced activity on extracellular electrode arrays, indicating that these transcriptional changes were sufficient to disrupt physiological neuronal function. These data are the first to characterize the consequence of H1.4 CFT in neurons. Our data provide initial insights into causes of neurodevelopmental impairments associated with these frameshift mutations in the C-terminus of H1.4 and highlight the need for future studies on the function of normal histone H1.4 in neurons.

Dataset Information

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature.

Background

Results

Conclusions

Publications

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature.

Similar Datasets

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