Novel DNMT3A germline mutations are associated with inherited Tatton‐Brown–Rahman syndrome

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 caus...

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Bibliographic Details
Published in:Clinical genetics 2017-04, Vol.91 (4), p.623-628
Main Authors: Xin, B., Cruz Marino, T., Szekely, J., Leblanc, J., Cechner, K., Sency, V., Wensel, C., Barabas, M., Therriault, V., Wang, H.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Canada
Child
clinical exome sequencing
DNA (Cytosine-5-)-Methyltransferases - genetics
DNMT3A
Exome - genetics
Facies
Female
Genetic disorders
Genetic Predisposition to Disease
Germ-Line Mutation - genetics
Heterozygote
Humans
Intellectual disabilities
Intellectual Disability - genetics
Intellectual Disability - physiopathology
Male
Middle Aged
Mutation
overgrowth
Pedigree
Sequence Analysis, DNA
Tatton‐Brown–Rahman syndrome
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Summary: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. Identification of two novel germline mutations in the DNMT3A gene associated with inherited Tatton‐Brown–Rahman syndrome (TBRS) in two North American families.
ISSN:0009-9163
1399-0004
DOI:10.1111/cge.12878