Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders

Gene: DNMT3A

Comment on list classification: I agree with the review - sufficient cases and phenotype is appropriate.

Created: 28 Apr 2018, 12:39 p.m.

Green List (high evidence)

Review and Green rating from Kate Tatton-Brown April 2017: mutations can be difficult to interpret because of clonal haematopoiesis: mechanism of pathogenesis not currently understood- LOF?

Created: 31 May 2019, 8:31 a.m.

Added DNMT3A as it was missing from the panel merge between Sotos syndrome panel with Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorders panel. DNMT3A is not a Sotos syndrome gene but (GeneReview: Sotos Syndrome PMID: 20301652) but Tatton-Brown et al. 2014 PMID:20301652 identified de novo variants in DNMT3A gene with patients indicating a new type of human overgrowth syndrome (OGID).
Also more recently (2017) Tatton-Brown et al (http://conf.hinxton.wellcome.ac.uk/advancedcourses/GRD2017Abstactbook.pdf) has explored the genetic architecture of human overgrowth syndromes and growth control, and performed experimental and bioinformatic analyses of 710 individuals with OGID, identifying patients with OGID-causing mutations in genes including NSD1 (240 cases), EZH2 (34 cases), DNMT3A (18 cases), CHD8 (12 cases) and EED (two cases) and HIST1H1E (five cases). Other genes with OGID-causing mutations, identified in the current study, include NFIX (14 cases), GPC3 (two cases) and BRWD3 (seven cases) in addition to the genes encoding components of the PI3K/AKT pathway (PTEN (16 cases); PPP2R5D (three cases); AKT and PIK3CA (one case each).

Created: 31 Mar 2017, 4:18 p.m.

Comment on phenotypes: added alternative synonyms

Created: 31 Mar 2017, 4:11 p.m.

Comment on publications: literature with new evidence to support green status

Created: 31 Mar 2017, 4:09 p.m.

Associated with phenotype in OMIM and G2P. Tatton-Brown–Rahman syndrome (TBRS) is a relatively new overgrowth syndrome described in 13 isolated cases (Tatton-Brown et al, 2014, PMID:24614070). This autosomal dominant condition is characterized by tall stature, intellectual disability and a distinctive facial appearance. De novo mutations in the DNA methyltransferase 3A (DNMT3A) gene were responsible for all 13 cases [PMID:24614070]. In 2016 Okamoto et al.PMID: 26866722 reported a new TBRS patient from Japan caused by de novo microdeletion of chromosome 2p23 including the DNMT3A gene.
More recently (2017) the first cases with inherited TBRS and the identification of novel germline mutations in the DNMT3A gene associated with the disease has been reported. B. Xin et al. (2017) PMID:27701732 describe six patients with TBRS and the identification of their underlying mutations in the DNMT3A gene. The patients were from two families of different ethnic background, an Old Order Amish in America and a French Canadian in Canada.They identified two novel mutations in DNMT3A : c.2312G>A (p.Arg771Gln) missense mutation in the Amish patients and a c.2296_2297delAA (p.Lys766Glufs*15) small deletion in the French Canadian patients. The mutations co-segregated consistently with the disease phenotype, with all affected individuals being heterozygous for their corresponding mutation, and none of the unaffected siblings carried the mutations.

Created: 31 Mar 2017, 4:03 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Tatton-Brown-Rahman syndrome, 615879; OVERGROWTH SYNDROME WITH INTELLECTUAL DISABILITY

Publications

• 24614070
• 26866722
• 27701732
• 20301652