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

Over five years, the Epigenetics and Chromatin Clinic at Johns Hopkins provided 741 visits for 432 patients, with 153 confirmed epigenetic diagnoses. All 115 patients with Mendelian disorders of the epigenetic machinery (MDEMs) had developmental delay or intellectual disability, and 70.4% had growth abnormalities. The clinic's high follow-up rate (62.5% in year 5) and role in discovering new disorders and advancing therapies highlight the value of specialized multidisciplinary care for these rare conditions.

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**Background** The Epigenetics and Chromatin Clinic (ECC) at Johns Hopkins was founded in 2012 to centralize care for patients with classical imprinting disorders and the emerging group of Mendelian disorders of the epigenetic machinery (MDEMs), also called Chromatinopathies. MDEMs result from pathogenic germline variants in genes encoding components of the epigenetic machinery (writers, erasers, readers, remodelers). The clinic's mission is threefold: (1) diagnose and provide optimal care, (2) learn fundamental truths about epigenetics to develop therapies, and (3) educate healthcare providers and patients. This paper reports on the clinic's experience over five years (July 2016–June 2021).

**Methods** ECC records from July 2016 through June 2021 were reviewed for diagnosis, genetic workup, growth parameters, neurodevelopmental features, and demographics. Postnatal growth abnormality was defined as absolute Z-score >2 in length/height on CDC charts. Neurodevelopmental diagnoses followed DSM-5 criteria. Patients were categorized as MDEM, Imprinting, Epigenetic other, Non-epigenetic, Undiagnosed, or None. MDEMs were strictly defined as disorders caused by disruption of genes encoding writer, eraser, remodeler, or reader domains.

**Key Results** Over five years, 741 visits were completed for 432 individual patients. Of these, 220 (50.9%) returned for at least one follow-up; by year 5, 62.5% of visits were follow-ups. Patients originated from 3 countries and 29 U.S. states; 26.9% resided outside Maryland. Demographics: 63.4% White/Caucasian, 14.8% Black/African American, 6.9% Asian/Pacific Islander, 14.8% other; 9.0% Hispanic/Latino; 47.7% male, 52.3% female; mean age 8.67 years (range 0–53).

Of 432 patients, 153 had confirmed epigenetic diagnoses: 115 (26.6%) with MDEMs, 36 (8.3%) with imprinting disorders, and 2 with other epigenetic disorders (Chromatinopathies). Among MDEMs, the top five diagnoses were Kabuki syndrome 1 (34 patients, 29.6%), Wiedemann-Steiner syndrome (14, 12.2%), Sotos syndrome (12, 10.4%), Arboleda-Tham syndrome (10, 8.7%), and Intellectual developmental disorder autosomal dominant 1 (7, 6.1%). In total, 26 distinct MDEMs were seen.

Every single one of the 115 MDEM patients had some neurodevelopmental disability. Cognitive levels: 18.3% mild impairments not meeting intellectual disability, 33.9% mild ID, 29.6% moderate ID, 18.3% severe/profound ID; 11.3% were nonverbal. Additional neurodevelopmental features: 38.3% had ADHD, 33.9% had anxiety, 8.7% had autism, 82.6% had hypotonia, and 20.9% had seizures. Growth abnormalities were present in 70.4%: 77.8% had growth retardation (56 with short stature, 35 with microcephaly, 28 with both) and 22.2% had overgrowth (13 tall stature, 14 macrocephaly, 9 both). Only 20.2% had abnormal birth growth parameters.

Molecularly, 58/115 (50%) were diagnosed by whole exome sequencing, 39 (34%) by single gene/panel testing, and the remainder by SNP microarray. Among the 26 MDEMs, 12 (46.2%) impacted writers, 6 (23%) erasers, 4 (15.4%) readers, and 3 (11.5%) remodelers; 61.5% involved dual-function components. Inheritance: 69.2% autosomal dominant, 19.2% X-linked, 3.8% autosomal recessive, 7.7% both dominant and recessive.

DNA methylation profiling (EpiSign) was used in six patients, confirming diagnoses (e.g., Temple syndrome, CHARGE syndrome, Kabuki syndrome 1 with mosaic variant) and ruling out pathogenicity in one case. The clinic facilitated discovery of two new disorders: Pilarowski-Bjornsson syndrome (CHD1) and Beck-Fahrner syndrome (TET3).

**Clinical Implications** The ECC demonstrates that specialized multidisciplinary care for MDEMs and imprinting disorders leads to high follow-up rates (62.5%) and low undiagnosed rates (27.5% vs. 65–75% nationally). The data confirm that intellectual disability and growth abnormalities are nearly universal in MDEMs, with hypotonia, ADHD, and anxiety also common. DNA methylation profiling is a valuable diagnostic tool, though insurance coverage remains a barrier. The clinic's ongoing clinical trial of the Modified Atkins diet in adults with Kabuki syndrome and other preclinical successes (HDAC inhibition, LSD1 inhibition) highlight the potential for postnatal therapeutic intervention. Expansion of multidisciplinary teams and collaboration with other epigenetics clinics will improve care and accessibility.

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other

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genetics

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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