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.

Attention challenges in Kabuki syndrome

“…In a review of a single clinic population of individuals with MDEMs including KS, ADHD was one of the most common features (Harris et al . 2023).…”

“…2019; Harris et al . 2023), mild to moderate intellectual disability (ID) (Niikawa et al . 1988) and speech and language deficits (Morgan et al .…”

“…Previously, our group found that 14 out of 34 individuals with molecularly confirmed KS1 seen in our clinic had a clinical diagnosis of ADHD (Harris et al . 2023). To expand upon this finding, we administered a set of parent‐reported and adult self‐reported questionnaires to 55 individuals with molecularly confirmed KS.…”

May the force be with you: Nuclear condensates function beyond transcription control

“…Mutations in chromatin regulators can lead to severe disorders that, due to their infrequent occurrence, are commonly referred to as rare CPs. [5,39] CPs represent a group of more than 80 human pathological conditions, which share some clinical features. These clinical evidence suggest that a shared abnormal biological process may be involved, causing common aberrant neurological development and growth abnormalities.…”

“…Mutations in chromatin regulators can lead to severe disorders known as chromatinopathies (CPs). [5] CPs are a heterogeneous group of rare Mendelian diseases caused by the haploinsufficiency of chromatin regulators involved in chromatin condensate organizations.…”