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

Andrea Ciolfi; Erfan Aref-Eshghi; Simone Pizzi; Lucia Pedace; Evelina Miele; Jennifer Kerkhof; Elisabetta Flex; Simone Martinelli; Francesca Clementina Radio; Claudia A L Ruivenkamp; Gijs W E Santen; Emilia Bijlsma; Daniela Barge-Schaapveld; Katrin Ounap; Victoria Mok Siu; R Frank Kooy; Bruno Dallapiccola; Bekim Sadikovic; Marco Tartaglia

doi:10.1186/s13148-019-0804-0

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

Clin Epigenetics. 2020 Jan 7;12(1):7. doi: 10.1186/s13148-019-0804-0.

Authors

Andrea Ciolfi¹, Erfan Aref-Eshghi^{2

3}, Simone Pizzi¹, Lucia Pedace⁴, Evelina Miele⁴, Jennifer Kerkhof^{2

3}, Elisabetta Flex⁵, Simone Martinelli⁵, Francesca Clementina Radio¹, Claudia A L Ruivenkamp⁶, Gijs W E Santen⁶, Emilia Bijlsma⁶, Daniela Barge-Schaapveld⁶, Katrin Ounap^{7

8}, Victoria Mok Siu⁹, R Frank Kooy¹⁰, Bruno Dallapiccola¹, Bekim Sadikovic^{11

12}, Marco Tartaglia¹³

Affiliations

¹ Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy.
² Department of Pathology and Laboratory Medicine, Western University, London, N6A 5C1, Canada.
³ Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, N6A 5W9, Canada.
⁴ Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy.
⁵ Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161, Rome, Italy.
⁶ Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2300, The Netherlands.
⁷ Department of Clinical Genetics, United Laboratories, Tartu University Hospital, 50406, Tartu, Estonia.
⁸ Institute of Clinical Medicine, University of Tartu, 50406, Tartu, Estonia.
⁹ Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, N6A 5W9, Canada.
¹⁰ Department of Medical Genetics, University of Antwerp, 2650, Antwerp, Belgium.
¹¹ Department of Pathology and Laboratory Medicine, Western University, London, N6A 5C1, Canada. bekim.sadikovic@lhsc.on.ca.
¹² Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, N6A 5W9, Canada. bekim.sadikovic@lhsc.on.ca.
¹³ Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy. marco.tartaglia@opbg.net.

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.

Keywords: Accelerated aging; Chromatin remodeling; DNA methylation; Episignature; HIST1H1E; Intellectual disability; Rahman syndrome; Replicative senescence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain / metabolism
DNA Methylation*
Developmental Disabilities / genetics*
Developmental Disabilities / metabolism
Epigenesis, Genetic
Frameshift Mutation*
Histones / genetics*
Humans
Intellectual Disability / genetics*
Intellectual Disability / metabolism
Neurons / metabolism
Signal Transduction / genetics
Syndrome

Substances

H1-4 protein, human
Histones