RESUMO
Tatton-Brown-Rahman syndrome (TBRS) was recently described in 13 isolated cases with de novo mutations in the DNMT3A gene. This autosomal dominant condition is characterized by tall stature, intellectual disability and a distinctive facial appearance. Here, we report six cases of inherited TBRS caused by novel DNMT3A germline mutations. The affected individuals belong to two sib-ships: four from an Old Order Amish family in America and two from a French Canadian family in Canada. All of them presented with characteristic features of TBRS, including dysmorphic facial features, increased height, intellectual disability, and variable additional features. We performed clinical exome sequencing and identified two mutations in the DNMT3A gene, a c.2312G>A (p.Arg771Gln) missense mutation in the Amish family and a c.2296_2297delAA (p.Lys766Glufs*15) small deletion in the French Canadian family. Parental DNA analysis by Sanger sequencing revealed that the Amish mutation was inherited from the healthy mosaic father. This study reflects the first cases with inherited TBRS and expands the phenotypic spectrum of TBRS.
