Identification of novel Mendelian disorders of the epigenetic machinery (MDEMs)-associated functional mutations and neurodevelopmental disorders

Background: Mendelian disorders of the epigenetic machinery (MDEMs) are a newly identified group of neurodevelopmental disorders (NDDs) and multiple congenital anomalies caused by mutations in genes encoding components of the epigenetic machinery. Many studies have shown that MDEM-associated mutations may disrupt the balance of chromatin states and trigger dysplasia. Aim: To help eight Chinese families with NDDs acquire a definitive diagnosis. Methods: In this study, we used whole-exome sequencing to diagnose eight unrelated Chinese families with NDDs. We also verified the potential pathogenic variants by Sanger sequencing and analyzed the changes in gene expression along with histone methylation modifications. Results: Eight variants of six epigenetic machinery genes were identified, six of which were novel. Six variants were pathogenic (P) or likely pathogenic (LP), while two novel missense variants (c.5113T>C in CHD1 and c.10444C>T in KMT2D) were classified to be variants of uncertain significance (VUS). Further functional studies verified that c.5113T>C in CHD1 results in decreased protein levels and increased chromatin modifications (H3K27me3). In addition, c.10444C>T in KMT2D led to a significant decrease in mRNA transcription and chromatin modifications (H3K4me1). Based on experimental evidence, these two VUS variants could be classified as LP. Conclusion: This study provided a definitive diagnosis of eight families with NDDs and expanded the mutation spectrum of MDEMs, enriching the pathogenesis study of variants in epigenetic machinery genes.