DNMT3A overgrowth syndrome is a disorder characterized by faster than normal growth before and after birth, subtle differences in facial features, and intellectual disability.
Individuals with DNMT3A overgrowth syndrome are often longer than normal at birth and are taller than their peers throughout life. Many affected individuals become overweight in late childhood or adolescence. They may also have an abnormally large head size (macrocephaly).
The characteristic facial appearance of individuals with DNMT3A overgrowth syndrome includes a round face; thick, horizontal eyebrows; and narrowed openings of the eyes (narrowed palpebral fissures). Additionally, the upper front teeth are often larger than normal.
Intellectual disability in DNMT3A overgrowth syndrome ranges from mild to severe. Individuals may have features of autism spectrum disorder, which are characterized by impaired communication and socialization skills.
Individuals with DNMT3A overgrowth syndrome may have other signs and symptoms, including a rounded upper back that also curves to the side (kyphoscoliosis), heart defects, flat feet (pes planus), weak muscle tone (hypotonia), or joints that are loose and very flexible (hypermobile joints). Psychological disorders such as depression, anxiety, or obsessive-compulsive disorder can also occur in this disorder.
The prevalence of DNMT3A overgrowth syndrome is unknown. More than 20 affected individuals have been described in the medical literature.
As its name suggests, mutations in the DNMT3A gene cause DNMT3A overgrowth syndrome. The DNMT3A gene provides instructions for making an enzyme called DNA methyltransferase 3 alpha. This enzyme is involved in DNA methylation, which is the addition of methyl groups, consisting of one carbon atom and three hydrogen atoms, to DNA molecules. DNA methylation is important in many cellular functions. These include regulating gene activity and certain chemical reactions and controlling the processing of chemicals that relay signals in the nervous system (neurotransmitters). DNA methyltransferase 3 alpha is particularly important for establishing DNA methylation patterns during development before birth.
Some DNMT3A gene mutations that cause DNMT3A overgrowth syndrome lead to a decrease in normal enzyme function. As a result, there is a reduction in DNA methylation, particularly affecting DNA methylation before birth. It is unclear how other mutations affect protein function. Decreased DNA methylation likely disrupts the normal regulation of important developmental genes, although how these change cause the specific features of DNMT3A overgrowth syndrome is unknown.
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.
Other Names for This Condition
- Tatton-Brown-Rahman syndrome
Additional Information & Resources
Genetic Testing Information
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
- Lemire G, Gauthier J, Soucy JF, Delrue MA. A case of familial transmission of the newly described DNMT3A-Overgrowth Syndrome. Am J Med Genet A. 2017 Jul;173(7):1887-1890. doi: 10.1002/ajmg.a.38119. Epub 2017 Apr 27. Citation on PubMed
- Okamoto N, Toribe Y, Shimojima K, Yamamoto T. Tatton-Brown-Rahman syndrome due to 2p23 microdeletion. Am J Med Genet A. 2016 May;170A(5):1339-42. doi: 10.1002/ajmg.a.37588. Epub 2016 Feb 11. Citation on PubMed
- Tatton-Brown K, Seal S, Ruark E, Harmer J, Ramsay E, Del Vecchio Duarte S, Zachariou A, Hanks S, O'Brien E, Aksglaede L, Baralle D, Dabir T, Gener B, Goudie D, Homfray T, Kumar A, Pilz DT, Selicorni A, Temple IK, Van Maldergem L, Yachelevich N; Childhood Overgrowth Consortium, van Montfort R, Rahman N. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014 Apr;46(4):385-8. doi: 10.1038/ng.2917. Epub 2014 Mar 9. Erratum in: Nat Genet. 2014 Jun;46(6):657. Citation on PubMed or Free article on PubMed Central
- Xin B, Cruz Marino T, Szekely J, Leblanc J, Cechner K, Sency V, Wensel C, Barabas M, Therriault V, Wang H. Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. Clin Genet. 2017 Apr;91(4):623-628. doi: 10.1111/cge.12878. Epub 2017 Jan 22. Citation on PubMed