RNA Sequencing and Pathway Analysis Identify Important Pathways Involved in Hypertrichosis and Intellectual Disability in Patients with Wiedemann–Steiner Syndrome

A growing number of histone modifiers are involved in human neurodevelopmental disorders, suggesting that proper regulation of chromatin state is essential for the development of the central nervous system. Among them, heterozygous de novo variants in KMT2A, a gene coding for histone methyltransferase, have been associated with Wiedemann–Steiner syndrome (WSS), a rare developmental disorder mainly characterized by intellectual disability (ID) and hypertrichosis. As KMT2A is known to regulate the expression of multiple target genes through methylation of lysine 4 of histone 3 (H3K4me), we sought to investigate the transcriptomic consequences of KMT2A variants involved in WSS. Using fibroblasts from four WSS patients harboring loss-of-function KMT2A variants, we performed RNA sequencing and identified a number of genes for which transcription was altered in KMT2A-mutated cells compared to the control ones. Strikingly, analysis of the pathways and biological functions significantly deregulated between patients with WSS and healthy individuals revealed a number of processes predicted to be altered that are relevant for hypertrichosis and intellectual disability, the cardinal signs of this disease.