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

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.

Fig. 1

Mendelian disorders of the epigenetic machinery (MDEMs). The 85 genes known to cause MDEMs are grouped based on whether they encode enzymatic writers, erasers, or remodelers or non-enzymatic readers (middle icons). Gray shading indicates dual function components that have a reader domain in addition to one of the above enzymatic domains. The small circles around the periphery denote inheritance pattern: dominant (filled circles), recessive (dot in center of circle), or dominant and recessive inheritance reported (half dot/half-filled circle). Genes associated with intellectual disability or growth abnormalities (growth retardation or overgrowth as defined in the text) are indicated with blue or orange shading around the periphery, respectively. In the inner circle, “A” or “X” denotes a gene’s location as being on an autosome or the X chromosome, respectively (adapted from Fahrner and Bjornsson 2019)

Fig. 2

Visits to the Epigenetics and Chromatin Clinic. Numbers and percentages of visits by year and type of visit. New visits are indicated with red shading, and follow-up visits are indicated with blue shading. Video visits are indicated with black diagonal lines. Year 1: July 2016-June 2017; Year 2: July 2017-June 2018; Year 3: July 2018-June 2019; Year 4: July 2019-June 2020; Year 5: July 2020-June 2021

Fig. 3

Geographic distribution of Epigenetics and Chromatin Clinic patients in the United States. Number of ECC patients residing in each state at the time of their visit(s) from July 2016 through June 2021. Colors represent the number of patients seen from the state: zero (light yellow); 1–5 (dark yellow); 6–10 (orange); 10–100 (orange red); more than 100 (dark red)

Fig. 4

Patient diagnoses in the Epigenetics and Chromatin Clinic. a Broad categories of diagnoses seen in the ECC from July 2016 through June 2021 include MDEMs (red), Imprinting (blue), and Epigenetic, Other (orange), which are categorized as epigenetic, as well as Non-epigenetic (purple), Undiagnosed (yellow), and None (aqua). Diagnosis types are defined in the text. b Top 5 MDEMs diagnosed July 2016 through June 2021. KS1 Kabuki syndrome 1 (red); WSS Wiedemann-Steiner syndrome (blue); SS Sotos syndrome (yellow); ATS Arboleda-Tham syndrome, also known as KAT6A-associated neurodevelopmental disorder or KAT6A syndrome (purple); MRD1 Intellectual development disorder, autosomal dominant 1, formerly known as Mental retardation, autosomal dominant 1 (orange). All other MDEM diagnoses (aqua)

Fig. 5

Neurodevelopmental phenotypes among Mendelian disorders of the epigenetic machinery seen in the Epigenetics and Chromatin Clinic. Number of individuals with each described neurodevelopmental phenotype among the 115 patients with MDEMs broken out by the 5 most common diagnoses and all others (aqua). KS1 Kabuki syndrome 1 (red); WSS Wiedemann-Steiner syndrome (blue); SS Sotos syndrome (yellow); ATS Arboleda-Tham syndrome (also known as KAT6A-associated neurodevelopmental disorder or KAT6A syndrome; purple); MRD1 Intellectual development disorder, autosomal dominant 1, formerly known as Mental retardation, autosomal dominant 1 (orange). It should be noted that quite a few of the individuals with the different syndromes were infants or toddlers and so their ADHD and anxiety phenotypes remain unknown

Fig. 6

Growth abnormalities observed in patients with Mendelian disorders of the epigenetic machinery in the Epigenetics and Chromatin Clinic. Venn diagram for a growth retardation and b overgrowth based on whether height, occipital-frontal head circumference (OFC), or both were affected. Numbers indicate the total number of affected individuals with each feature; gene names indicate the epigenetic machinery component disrupted. *Indicates gene unknown. This is the case for Kabuki-Turner syndrome (KTS), as its molecular etiology is not known, and for Kabuki syndrome not otherwise specified (KS NOS), as the individual met clinical criteria for KS, but no pathogenic variant was identified in either gene that causes KS (KMT2D or KDM6A). + indicates that the affected individual had a pathogenic variant in another gene in addition to EP300. Parentheses indicate that for these genes, overgrowth is not typically observed. Only 18/89 individuals with MDEMs (20.2%) exhibited abnormalities in birth growth parameters; however, information was unavailable for 26 individuals

Fig. 7

Components of the epigenetic machinery disrupted in patients from the Epigenetics and Chromatin Clinic. Functions of the epigenetic machinery implicated in the 26 Mendelian disorders of the epigenetic machinery seen in the ECC from July 2016 through June 2021. Proportion of each category: writers (red); erasers (blue); readers (yellow); and remodelers (orange). Purple indicates that the epigenetic machinery component function is unknown. The proportion of each enzymatic component (writer, eraser, remodeler) with dual function (i.e., with an accompanying reader domain) is indicated with black dots. The numbers correspond to the disorders listed in Table 2