Convergent DNA Methylation Abnormalities at Enhancers and Bivalent Chromatin in Human Growth Disorders [RNA-seq]

Overgrowth with Intellectual Disability (OGID) is characterized by generalized overgrowth, including a head circumference and/or height ≥ 2 standard deviations (s.d.) above the mean, accompanied by mild to moderate intellectual disability. Sotos Syndrome, the most common form of OGID, results from loss-of-function (LoF) mutations in NSD1, which encodes a histone methyltransferase. Another major OGID subtype, Tatton-Brown-Rahman syndrome, is caused by LoF mutations in DNMT3A, encoding a de novo DNA methyltransferase. In contrast, gain-of-function (GoF) mutations in DNMT3A cause Heyn-Sproul-Jackson syndrome, characterized by growth restriction and microcephaly. We hypothesize that NSD1 LoF and DNMT3A LoF mutations share a convergent DNA methylation signature that is distinct from the pattern seen in DNMT3A GoF mutations. To test this, we generated human embryonic stem cell lines carrying these growth syndrome-associated mutations in NSD1 and DNMT3A, profiled their DNA methylation patterns using the Illumina EPIC array, and analyzed both shared and unique methylation phenotypes.