Mutations in MAP3K7 that alter the activity of the TAK1 signaling complex cause frontometaphyseal dysplasia

<B>Full-text article is free to read on the publisher's website</B>\ud \ud Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in <i>FLNA</i>, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in <i>FLNA</i> and are phenotypically very similar to individuals with <i>FLNA</i> mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable <i>FLNA</i> mutation, we identified mutations in two genes—<i>MAP3K7</i>, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and <i>TAB2</i>, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in <i>MAP3K7</i>, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in <i>TAB2</i> (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by <i>FLNA</i> mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by <i>FLNA</i> mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex

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 disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novo DNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in &gt;80% of individuals with 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 eyebrows and 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 individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS