ClinGen Dosage Sensitivity Curation Page

DNMT3A

  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
24614070 Tatton-Brown et al. (2014) initially detected a total of 13 de novo DNMT3A variants among individuals with overgrowth disorders. There are 10 nonsynonymous mutations, two small frameshifting insertions and one inframe deletion. The variants are all located in functional domain that involved with domain-domain interactions and histone binding. The two frameshift variants are located in exon 8 and 19 respectively (of 23 total exons). The authors discussed that the mechanism of pathogenesis in DNMT3A overgrowth syndrome as ?It is currently unclear though a simple haploinsufficiency model appears unlikely given the small proportion of truncating mutations".
26866722 Okamoto et al. (2-16) reported a submicroscopic deletion of chromosome 2p23 including DNMT3A in a patient with overgrowth phenotypes that were consistent with those of Tatton-Brown-Rahman syndrome. It was a de novo 1.5Mb deletion (chr2:24,012,152?25,552,894). There are 15 genes involved within the deletion. The POMC gene which encode proopiomelanocortin was also deleted. The authors also discussed three previously reported deletion cases (22246919; 23142270; 24700699) at this loci in patients with postnatal overgrowth and/or obesity. POMC was suspected as possibly associated with obesity phenotypes (with no mentioning of potential role of DNMT3A). No deletion cases is reported in DGV gold standard database, but there are five exonic deletions in DDD controls. There are other deletion cases involving DNMT3A in DECIPHER that did not list overgrowth as one of the features.
27701732 Xin et al. (2017) reported two novel variants in DNMT3A, one c.2312G>A (p.Arg771Gln) missense and another c.2296_2297delAA (p.Lys766Glufs*15)(in exon 19/23) small deletion in two families. The variants co-segregated with Tatton-Brown?Rahman syndrome phenotypes in multiple individuals in each family. The missense variant was inherited from mosaic unaffected father. The small deletion was of unknown origin (father deceased, not inherited from mother) .

Haploinsufficiency phenotype comments:

Germline mutations in DNMT3A are known to cause Tatton-Brown-Rahman syndrome which is characterized by tall stature, a distinctive facial appearance (round face, heavy horizontal eyebrows, and narrow palpebral fissures), and intellectual disability. It was initially described by Tatton-Brown et al. (2014) among 13 individuals with simialr overgrowth syndrome and de novo DNMT3A (the DNA methyltransferase 3A gene) mutations. There are 10 nonsynonymous mutations, two small frameshifting insertions and one inframe deletion. The variants are all located in functional domain that involved with domain-domain interactions and histone binding. the authors discussed that the mechanism of pathogenesis in DNMT3A overgrowth syndrome was unclear though a simple haploinsufficiency model appears unlikely given the small proportion of truncating mutations. Okamoto et al.(2016) reported a submicroscopic deletion of chromosome 2p23 including DNMT3A in a patient with overgrowth phenotypes that were consistent with those of Tatton-Brown-Rahman syndrome. Kosaki et al.(27991732), Hollink et al. (28432085) and Shen et al. (28941052)(2017) reported a missense mutation (Arg882) among Tatton-Brown-Rahman overgrowth syndrome patients, the mutation is a well known somatic mutation hotspot in DNMT3A in acute myeloid leukemia (AML) patients. It is now demonstrated by mouse modeling (27841873) that this hotspot mutation contributed to AML pathogenesis by a dominant negative mechanism. Xin et al. (2017) reported two novel variants in DNMT3A, one c.2312G>A (p.Arg771Gln) missense and another c.2296_2297delAA (p.Lys766Glufs*15) small deletion in two families. The variants cosegregated with Tatton-Brown?Rahman syndrome phenotypes in multiple individuals in each family. The missense variant was inherited from mosaic unaffected father. The small deletion was of unknown origin (father deceased, not from mother) . Additionally Lemire et al. (2017) reported a case of familial transmission of A heterozygous splice site mutation NM_022552.4 (DNMT3A): c.2323-2A?>?T in a family with Tatton-Brown-Rahman Syndrome. The affected father passed the mutation to two affected siblings. Dew? et al.(2017) reported a 7.4Mb deletion at 2p23.2-p24.1 in a a 10-year-old boy, 58 kg (>97th centile obsese) and 1.45 m tall (82th centile) with psychomotor retardation, hyperphagia, macrosomia, narrow forehead, and thick eyebrows. In several microdeletions involving 2p23 previously reported by Shoukier et al., (PMID: 22246919), Rocca et al., (PMID: 23142270) and Bloch et al., (PMID: 24700699), the patients had overgrowth phenotype, as the one reported by Okamoto. yet there are other deletions in DECIPHER at the region did not report overgrowth pehnotype. The HI was predicted to be 3.99%, the pLI is 0 (there are 55 observed LOF variants but most of them are questionable judging from the skewed heterozygocity status-could they all be mosiac/somatic?). There are five exonic deletion cases in control samples in DDD study, no deletion in gold standard DGV database. Overall, the mechanism of Tatton-Brown-Rahman has not been fully elucidated at this time, and there is no sufficient evidence to support the haploinsufficiency of DNMT3A gene, yet we cannot definitively rule out the possibility of LOF. We felt a score of 1 for haploinsufficiency is most appropriate at this time so additional evidence should be sought and evaluated.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity