Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Hum Genet. 2024 Apr;143(4):607-624. doi: 10.1007/s00439-023-02537-1. Epub 2023 Mar 23.
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.
约翰霍普金斯大学的多学科表观遗传学和染色质诊所为涉及表观遗传学紊乱的罕见疾病患者提供全面的医疗护理。该诊所最初专注于经典印迹障碍，后来将重点转移到由表观遗传机制基因中的致病变异体导致的新兴遗传疾病群体。这些疾病统称为表观遗传机制的孟德尔疾病（MDEMs），或更广泛地称为染色质病。在五年内，为 432 名个体患者完成了 741 次就诊，其中 153 人被确诊为表观遗传疾病。在这些患者中，有 115 人患有 26 种 MDEMs 中的一种，所有这些患者都表现出全面发育迟缓或智力残疾。这支持了先前的观察结果，即智力残疾是 MDEMs 最常见的表型特征。我们诊所中其他常见的表型包括生长异常和神经发育问题，特别是肌张力低下、注意力缺陷/多动障碍（ADHD）和焦虑症，癫痫发作和自闭症则较少见。总的来说，我们的患者群体代表了更广泛的 MDEMs 群体，包括主要影响作家的常染色体显性疾病，而不是影响橡皮擦、染色质标记的读取器和重塑器的疾病。双功能组件（具有读取器和酶结构域的组件）的代表比例增加。正如预期的那样，诊断主要是通过测序做出的，但在某些情况下，DNA 甲基化分析也提供了帮助。我们的诊所帮助发现了两种新疾病，我们的医生正在积极为 MDEMs 开发和实施新的治疗策略。这些数据和我们超过 60%的高随访率表明，我们正在实现我们的使命，为有表观遗传学紊乱的患者进行诊断、学习和提供最佳护理。
