Genome-wide DNA methylation profiling confirms a case of low-level mosaic Kabuki syndrome 1

Kabuki syndrome is a Mendelian disorder of the epigenetic machinery characterized by typical dysmorphic features, intellectual disability, and postnatal growth deficiency. Pathogenic variants in the genes encoding the chromatin modifiers KMT2D and KDM6A are responsible for Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), respectively. In addition, 11 cases of KS1 caused by mosaic variants in KMT2D have been reported in the literature. Some of these individuals display milder craniofacial and growth phenotypes, and most do not have congenital heart defects. We report the case of an infant with severe hypoplastic left heart syndrome with mitral atresia and aortic atresia (HLHS MA-AA), pulmonary vein stenosis, and atypical facies with a somatic mosaic de novo nonsense variant in KMT2D (c.8200C\u3eT, p.R2734*) identified on trio exome sequencing of peripheral blood and present in 11.2% of sequencing reads. KS was confirmed with EpiSign, a diagnostic genome-wide DNA methylation platform used to identify epigenetic signatures. This case suggests that use of this newly available clinical test can guide the interpretation of low-level mosaic variants identified through sequencing and suggests a new lower limit of mosaicism in whole blood required for a diagnosis of KS

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

Funding Information: None of the authors had specific funding for this publication, but JRH is supported by grants from the NIH/NICHD 1K23HD101646, the Kabuki Syndrome Foundation, the Rubinstein-Taybi Syndrome Children’s Foundation, the Sekel-Breidenstein Family Fund, and the Kennedy Krieger IDDRC NIH P50HD103538. HTB is supported by the Louma G. Foundation, the Icelandic Research Fund (#217988, #195835, #206806) and the Icelandic Technology Development Fund (#2010588), and JAF is supported by the National Institutes of Health, specifically the National Institute for Child Health and Human Development (NICHD; K08HD086250), the Maryland Stem Cell Research Fund (2022-MSCRFL-5846), and a Johns Hopkins Catalyst Award. CWG receives support from NIH T32GM136577. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.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.Peer reviewe