NSD 1 , EZH 2 and DNMT 3 A Overgrowth Genes and Their Associated Overgrowth Syndromes

Abstract

Abstract Nuclear receptor SET‐domain containing protein 1 ( NSD1 ), Enhancer of Zeste, drosophila, Homolog 2 ( EZH2 ) and DNA methyltransferase 3A ( DNMT3A ) constitute an emerging family of epigenetic regulatory genes with a dual somatic/germline role in the pathogenesis of haematological malignancies and overgrowth disorders. NSD1 , EZH2 and DNMT3A all encode components of the epigenetic arsenal and are involved in the regulation of transcription: both NSD1 and EZH2 are histone methyltransferases whilst DNMT3A is a DNA methyltransferase. The three overgrowth disorders caused by germline mutations of NSD1 , EZH2 and DNMT3A , Sotos syndrome, Weaver syndrome and the DNMT3A overgrowth disorder, respectively, are all characterised by pre‐ and postnatal increased growth, a variable intellectual disability and a distinctive, syndrome‐specific but often subtle facial appearance. However, despite the vast increase in knowledge over the last decade, there are still many questions about this new family of overgrowth genes that remain unanswered and further clinical and molecular studies are underway to try to address these. Key Concepts: NSD1 , EZH2 and DNMT3A are all overgrowth genes with a dual somatic/germline role in the pathogenesis of haematological malignancies/overgrowth disorders. NSD1, EZH2 and DNMT3A all have a role in the regulation of the epigenome. Germline NSD1 gene abnormalities causes Sotos syndrome, germline EZH2 gene abnormalities cause Weaver syndrome and the DNMT3A overgrowth syndrome is caused by germline DNMT3A gene abnormalities. Sotos syndrome, Weaver syndrome and the DNMT3A overgrowth syndrome are all characterised by postnatal overgrowth (height and/or head circumference at least two standard deviations above the mean); a variable learning disability and a distinctive, but often subtle, facial appearance. Other overgrowth conditions which should be considered in the differential diagnosis of Sotos, Weaver and the DNMT3A overgrowth syndromes include the PTEN hamartoma tumours spectrum, Simpson–Golabi–Behmel syndrome, Beckwith–Wiedemann syndrome and the overgrowth disorder associated with NFIX mutations.