SEARCHCOHORTpediatrics, internal medicine

cohort·pediatrics, internal medicine, clinical trial, observational study, biomedical research·PMC10034257

Five years of experience in the Epigenetics and Chromatin Clinic: what have we learned and where do we go from here?

Human Genetics · 6 authors, 7 centres

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TL;DR

This retrospective cohort study describes the five-year experience of a multidisciplinary clinic for rare epigenetic disorders, focusing on 115 patients with confirmed Mendelian disorders of the epigenetic machinery (MDEMs). The central result is that global developmental delay and/or intellectual disability was present in every single one of these 115 patients, confirming it as a core feature of this disease group.

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This retrospective cohort study analyzed clinical records from 432 patients evaluated over five years at the Epigenetics and Chromatin Clinic. The key finding is that all 115 patients with an MDEM exhibited global developmental delay and/or intellectual disability. Common additional features included growth abnormalities, hypotonia, ADHD, and anxiety. The cohort was representative of known MDEMs, being predominantly autosomal dominant disorders affecting 'writer' proteins. Limitations include potential referral bias, as developmental delay was a referral criterion, and incomplete longitudinal anthropometric data, particularly for overgrowth phenotypes.

STUDY TYPE

cohort

SPECIALTY

pediatrics

SUMMARISED BY

AI pipeline

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ORIGINAL PAPER

PMC10034257

Five years of experience in the Epigenetics and Chromatin Clinic: what have we learned and where do we go from here?

Human Genetics

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ABSTRACT

The multidisciplinary Epigenetics and Chromatin Clinic at Johns Hopkins provides comprehensive medical care for individuals with rare disorders that involve disrupted epigenetics. Initially centered on classical imprinting disorders, the focus shifted to the rapidly emerging group of genetic disorders resulting from pathogenic germline variants in epigenetic machinery genes. These are collectively called the Mendelian disorders of the epigenetic machinery (MDEMs), or more broadly, Chromatinopathies. In five years, 741 clinic visits have been completed for 432 individual patients, with 153 having confirmed epigenetic diagnoses. Of these, 115 individuals have one of 26 MDEMs with every single one exhibiting global developmental delay and/or intellectual disability. This supports prior observations that intellectual disability is the most common phenotypic feature of MDEMs. Additional common phenotypes in our clinic include growth abnormalities and neurodevelopmental issues, particularly hypotonia, attention-deficit/hyperactivity disorder (ADHD), and anxiety, with seizures and autism being less common. Overall, our patient population is representative of the broader group of MDEMs and includes mostly autosomal dominant disorders impacting writers more so than erasers, readers, and remodelers of chromatin marks. There is an increased representation of dual function components with a reader and an enzymatic domain. As expected, diagnoses were made mostly by sequencing but were aided in some cases by DNA methylation profiling. Our clinic has helped to facilitate the discovery of two new disorders, and our providers are actively developing and implementing novel therapeutic strategies for MDEMs. These data and our high follow-up rate of over 60% suggest that we are achieving our mission to diagnose, learn from, and provide optimal care for our patients with disrupted epigenetics.

CITATION EXPORT

Jacqueline R. Harris, Christine W. Gao, Jacquelyn F. Britton et al.. Five years of experience in the Epigenetics and Chromatin Clinic: what have we learned and where do we go from here?. Human Genetics. (2023). https://doi.org/10.1007/s00439-023-02537-1

AUTHORS

6 · 7 CENTRES

Jacqueline R. Harris, Christine W. Gao, Jacquelyn F. Britton, Carolyn D. Applegate, Hans T. Bjornsson, Jill A. Fahrner

1grid.21107.350000 0001 2171 9311Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD USA
2grid.21107.350000 0001 2171 9311Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD USA
3grid.240023.70000 0004 0427 667XKennedy Krieger Institute, Baltimore, MD USA
4grid.21107.350000 0001 2171 9311Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD USA
5grid.21107.350000 0001 2171 9311Johns Hopkins Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD USA
6grid.14013.370000 0004 0640 0021Faculty of Medicine, University of Iceland, Reykjavik, Iceland
7grid.410540.40000 0000 9894 0842Landspitali University Hospital, Reykjavik, Iceland