The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A- overgrowth syndrome, is an overgrowth intellectual disabilitysyndrome first described in 2014 with a report of 13 individualswith constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individualswith de novo DNMT3A variants, including the 13 previously reported individuals. An intellectual disabilityand overgrowth were reported in >80% of individualswith TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrowsand prominent upper central incisors; joint hypermobility(74%); obesity (weight ³2SD, 67%); hypotonia(54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis(33%) and afebrile seizures (22%). One individualwas diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individualswith TBRS