Clinical characteristics.

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth / intellectual disability syndrome characterized by length/height and/or head circumference ≥2 standard deviations above the mean for age and sex, obesity / increased weight, intellectual disability that ranges from mild to severe, joint hypermobility, hypotonia, behavioral/psychiatric issues, kyphoscoliosis, and seizures. Individuals with TBRS have subtle dysmorphic features, including a round face with coarse features, thick horizontal low-set eyebrows, narrow (as measured vertically) palpebral fissures, and prominent upper central incisors. The facial gestalt is most easily recognizable in the teenage years. TBRS may be associated with an increased risk of developing acute myeloid leukemia. There are less clear associations with aortic root dilatation and increased risk of other hematologic and solid tumors.

Diagnosis/testing.

The diagnosis of TBRS is established in a proband with suggestive findings and a heterozygous pathogenic variant in DNMT3A identified by molecular genetic testing

Management.

Treatment of manifestations: Treatments are primarily supportive and based on symptoms. Developmental delay / intellectual disability, behavioral/psychiatric diagnoses, epilepsy, joint hypermobility, kyphoscoliosis, sleep apnea, cryptorchidism, and acute leukemia are all treated in the standardized fashion.

Surveillance: Monitoring of growth parameters, developmental progress, behavior, mobility, and self-help skills at each visit. Assessment for new neurologic manifestations, seizures, and signs and symptoms of sleep apnea and hematologic malignancies at each visit. Low threshold for complete blood count with differential and further investigations in those who have concerning signs and symptoms of hematologic malignancy; there are no consensus guidelines regarding screening for hematologic malignancy in individuals with TBRS.

Genetic counseling.

TBRS is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with TBRS have the disorder as the result of a DNMT3A pathogenic variant inherited from a parent. Each child of an individual with TBRS has a 50% chance of inheriting the DNMT3A pathogenic variant. Once the DNMT3A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

TBRS should be considered in individuals with the following clinical findings and family history.

Clinical findings

• Generalized overgrowth (length/height and/or head circumference ≥2 standard deviations above the mean for age and sex) [Tatton-Brown et al 2017]
• Mild-to-severe developmental delay (DD) or intellectual disability (ID)

AND

• Any of the following features presenting in infancy or childhood/adolescence:
  • Dysmorphic facial features (See Clinical Characteristics.)
  • Joint hypermobility
  • Hypotonia
  • Kyphoscoliosis
  • Seizures, including variable afebrile seizure types
  • Cryptorchidism
  • Behavior problems, most commonly autism spectrum disorder, although a variety of behavioral issues have been described (See Clinical Characteristics.)
  • Acute myeloid leukemia and possibly other hematologic malignancies

Family history. Because TBRS is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e. a single occurrence in a family). However, there are individual reports of familial cases, including inheritance from an unaffected mosaic parent [Xin et al 2017, Balci et al 2020] and inheritance from an affected parent [Lemire et al 2017], suggesting rare autosomal dominant inheritance.

Establishing the Diagnosis

The diagnosis of TBRS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in DNMT3A identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous DNMT3A variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of TBRS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The cardinal features of Tatton-Brown-Rahman syndrome (TBRS) are overgrowth and mild-to-severe intellectual disability. Other common features include joint hypermobility, obesity / increased weight, hypotonia, behavioral/psychiatric problems, kyphoscoliosis, and seizures. To date, more than 90 individuals with a pathogenic variant in DNMT3A have been reported [Tatton-Brown et al 2014, Tlemsani et al 2016, Kosaki et al 2017, Lemire et al 2017, Shen et al 2017, Xin et al 2017, Tatton-Brown et al 2018, Sweeney et al 2019, Balci et al 2020, Hage et al 2020, Tenorio et al 2020, Yokoi et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports and the authors' personal communications with the families.

Growth. Overgrowth is present in more than 80% of affected individuals. However, clinical variability is seen among affected individuals and the absence of overgrowth does not preclude a diagnosis of TBRS.

• Tall stature (height ≥2 standard deviations [SD] above the mean for age and sex) is present in about 70% of individuals. Height ranges from 0.3 SD below to 6 SD above the mean.
• Macrocephaly (head circumference ≥2 SD above the mean for age and sex) is present in around 50% of affected individuals. Head circumference ranges from 1.2 SD below to 8.0 SD above the mean.
• About 65% of affected individuals are overweight or obese (weight ≥2 SD above the mean for age and sex). Weight ranges from 1.1 SD below to 4.5 SD above the mean.

There is relatively little information about birth measurements, although overgrowth typically is present from early childhood. In those for whom measurements were available, mean birth weight was 1.3 SD above the mean (range: 1.1 SD below to 4.0 SD above mean), mean birth head circumference was 2.3 SD above the mean (range: 0.6 to 6.5 SD above mean), and mean birth length was 1.6 SD above the mean (range: 0.0 to 4.4 SD above mean) [Tatton-Brown et al 2018].

Developmental delay (DD) and intellectual disability (ID). All affected individuals reported to date have some degree of developmental delay and/or intellectual disability, ranging from mild to severe. While the specific severity is not reported for all known individuals, most of those who are described in detail (n=83) had intellectual disability in the mild-to-moderate range.

• Mild ID (23/83, 28%). Children attend mainstream school and need some extra help – for example, a statement of educational needs (see Management) – but would be expected to live independently as adults and may have their own family.
• Moderate ID (48/83, 58%). Children develop speech and may be able to attend mainstream school with a high level of support, but more likely will attend a school or be in a program for individuals with special educational needs. While unlikely to live completely independently as adults, they may live in sheltered accommodation or with some additional support.
• Severe ID (12/83, 14%). Individuals require special education during schooling and are likely to require considerable support in adulthood.

A subsequent publication reported more detailed cognitive and behavioral profiles of a smaller cohort (n=18, age 7-33 years) [Lane et al 2020]. The mean General Conceptual Ability score was 53 (range: 39-76). Nonverbal and spatial reasoning were more significantly impaired than verbal reasoning.

Behavior problems. The behavior problems seen in individuals with TBRS are most commonly associated with autism spectrum disorder.

• In a series of 18 individuals with a confirmed molecular diagnosis, autistic traits were present in the majority, and eight (44%) fulfilled the ADOS-2 criteria for a formal diagnosis of autism [Lane et al 2020].
• The prevalence of autistic traits was lower in older individuals, suggesting that symptoms may improve with age, but this is based on cross-sectional assessment of a relatively small cohort rather than long-term observation.

Other behavior problems reported in a smaller proportion of affected individuals include [Tatton-Brown et al 2018, Tenorio et al 2020]:

• Anxiety
• Aggression
• Psychotic disorders
• Bipolar disorder
• Obsessive behaviors
• Compulsive eating

Musculoskeletal features. Generalized joint hypermobility is a common feature of TBRS. It can be associated with musculoskeletal pain and joint instability; joint dislocations are rare. Kyphoscoliosis is present in about 30% of affected individuals [Tatton-Brown et al 2018]. Widely spaced toes are a commonly reported feature, although the exact prevalence is unknown [Tatton-Brown et al 2018].

Hypotonia is present in a majority of individuals with TBRS [Tatton-Brown et al 2018] and may require physical therapy.

Epilepsy. Seizures are present in around 20% of people with TBRS [Tatton-Brown et al 2018]. Both febrile and afebrile seizures have been reported. There is limited information regarding the specific types of seizures, age of seizure onset, or whether specific anti-seizure medications are more effective than others in individuals with TBRS.

Neuroimaging. No specific or consistent imaging abnormalities are known to be characteristic of TBRS. Individual abnormalities detected on brain MRI have included ventriculomegaly and Chiari malformation [Kosaki et al 2017, Tatton-Brown et al 2018].

Genitourinary abnormalities. Cryptorchidism is present in about 20% of males with TBRS [Tatton-Brown et al 2018]. Other genitourinary abnormalities reported in a few individuals with TBRS include vesicoureteral reflux and hypospadias [Tatton-Brown et al 2018, Tenorio et al 2020].

Malignant tumors. There is evidence that the spectrum of germline DNMT3A pathogenic variants found in individuals with TBRS is similar to that found in sporadic, nonsyndromic malignancies [Shen et al 2017]. However, data are insufficient to determine the precise risk of malignancy to a given individual with TBRS. To date, hematologic malignancies have been reported in eight individuals with TBRS, suggesting a risk on the order of about 4% [Hollink et al 2017, Ferris et al 2022] (see Genotype-Phenotype Correlations and Cancer and Benign Tumors).

• The most common malignancy is acute myeloid leukemia (AML; 4/8 individuals); cases of lymphoid malignancy and myelodysplastic syndrome have also been reported.
• The median age at diagnosis is 9.6 years (range: age 2.5-12 years), with the cases of AML diagnosed between ages nine and 20 years.
• Limited information exists regarding lifetime cancer risk in individuals with TBRS, as the majority of individuals identified to date who have developed cancer are children or young adults.

Single case reports of a specific cancer in an individual with TBRS have been published; however, in the absence of further known cases, it is not clear whether these tumors are specifically associated with TBRS or are rare co-occurrences. The tumors are as follows:

• Neuroblastoma [Tenorio et al 2020]
• Medulloblastoma [Sweeney et al 2019]
• Benign glioma [Tenorio et al 2020]
• Acromegaly as a result of a pituitary adenoma [Hage et al 2020]
• Ganglioneuroblastoma and T-cell lymphoblastic lymphoma [Balci et al 2020]; this individual also had a truncating pathogenic variant in CLTC.

Facial features. While the facial gestalt of TBRS may not be as clinically recognizable as other overgrowth disorders (e.g., Sotos syndrome), common facial features are shared by a significant proportion of affected individuals. The facial features are most characteristic in adolescence and less specific in early childhood or adulthood. They include the following [Tatton-Brown et al 2018]:

• A round face with coarse features (describing some loss of definition of the nose, lips, mouth, and chin because of rounded and heavy features)
• Thick horizontal low-set (i.e., closer than anticipated to the orbit) eyebrows
• Narrow (as measured vertically) palpebral fissures
• Prominent upper central incisors

Other associated features. The following are less common features seen in affected individuals, including features reported in only one affected individual each. It remains to be confirmed whether the feature is specifically associated with TBRS or is a rare co-occurrence.

• Cardiovascular disease. Aortic root dilatation has been reported in several individuals with TBRS [Tatton-Brown et al 2018, Tenorio et al 2020, Cecchi et al 2022]. Aortic dissection and sudden cardiac death have not been reported, and it remains to be established whether aortic dilatation is static or progressive. Congenital heart defects (atrial septal defect, ventricular septal defect, persistent ductus arteriosus) are also commonly reported by families (although not yet published as a frequent association in the literature). A longitudinal study is under way to quantify the incidence. Less common cardiovascular features, reported in one affected individual each, include the following [Kosaki et al 2017, Tatton-Brown et al 2018, Cecchi et al 2022]:
  • Mitral valve prolapse
  • Dilated cardiomyopathy
  • Arrhythmia
• Respiratory abnormalities. Central sleep apnea has been reported in several individuals with TBRS [Tatton-Brown et al 2018, Balci et al 2020].
• Dental anomalies including malocclusion, caries, and double teeth have been reported in individuals with TBRS [Tatton-Brown et al 2018, Paz-Alegría et al 2020].
• Congenital diaphragmatic hernia has been described in one affected individual [Balci et al 2020].
• Autonomic dysfunction including postural orthostatic hypotension and episodic vasomotor instability in the extremities have been reported in four affected individuals [Balci et al 2020].

Prognosis. Data on whether TBRS alters life span are limited. Since many adults with disabilities have not undergone advanced genetic testing and mutation of DNMT3A was first recognized to be associated with a clinical phenotype in 2014 [Tatton-Brown et al 2014], it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

Malignancy. As in the case of sporadic, nonsyndromic malignancies (see Cancer and Benign Tumors), the most commonly observed pathogenic variants in individuals with TBRS who develop malignancy (n=8) are missense variants affecting the arginine residue at position 882 (Arg882 or R882), present in five of the eight affected individuals in whom malignancy occurred. This suggests that germline pathogenic variants affecting this residue may be particularly associated with an increased risk of malignancy (see Molecular Genetics).

Psychiatric issues. While there are relatively few reports of psychotic symptoms in individuals with TBRS, when psychotic symptoms have been reported, the majority of individuals (4/5) have pathogenic missense variants clustering within the methyltransferase domain of DNMT3A [Tatton-Brown et al 2018, Tenorio et al 2020] (see Molecular Genetics).

Prevalence

The prevalence of TBRS is unknown. More than 90 cases have been reported in the literature to date [Tatton-Brown et al 2014, Tlemsani et al 2016, Kosaki et al 2017, Lemire et al 2017, Shen et al 2017, Xin et al 2017, Tatton-Brown et al 2018, Sweeney et al 2019, Balci et al 2020, Hage et al 2020, Tenorio et al 2020, Yokoi et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TBRS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Tatton-Brown-Rahman syndrome (TBRS) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Nearly all probands reported to date with TBRS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo DNMT3A pathogenic variant.
• Rarely, individuals diagnosed with TBRS have the disorder as the result of a DNMT3A pathogenic variant inherited from a parent. Reports describing parental transmission of a pathogenic variant include inheritance from an unaffected mosaic parent [Xin et al 2017, Balci et al 2020] and from an affected parent [Lemire et al 2017].
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. * Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * A parent with somatic and germline mosaicism for a DNMT3A pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the DNMT3A pathogenic variant identified in the proband, the risk to sibs of inheriting the variant is 50%.
• If the DNMT3A pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental germline mosaicism [Xin et al 2017].

Offspring of a proband. Each child of an individual with TBRS has a 50% chance of inheriting the DNMT3A pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the DNMT3A pathogenic variant, members of the parent's family may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the DNMT3A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

DNMT3A encodes one of a family of DNA methyltransferases that catalyze the methylation of cytosine residues to 5-methylcytosine. The DMNT3A enzyme plays a role in establishment of parent-of-origin methylation during gametogenesis [Kaneda et al 2004] and reestablishment of methylation during embryogenesis [Okano et al 1999].

Methylation studies in mouse models and humans have demonstrated that TBRS pathogenic variants (including pathogenic missense variants, truncating variants, and whole-gene deletion) are associated with a characteristic hypomethylation pattern, indicating that these pathogenic variants cause loss of methyltransferase activity [Smith et al 2021]. This is likely to have widespread effects on gene expression.

Truncating variants, splice site variants, and whole-gene deletions are assumed to cause disease as a result of haploinsufficiency. The pathogenic missense variants reported to date are clustered within the three functional domains of DNMT3A (proline-tryptophan-tryptophan-proline [PWWP] domain, ATRX-DNMT3A-DNMT3L-type zinc finger [ADD] domain, and DNA methyltransferase domain), suggesting that they are likely to cause disease by affecting the function of these domains [Tatton-Brown et al 2018, Tenorio et al 2020]. This mechanism is supported by the observation that pathogenic missense variants are associated with a similar pattern of hypomethylation compared to loss-of-function pathogenic variants [Smith et al 2021]. There is evidence that, in addition to reducing activity of the mutated DNMT3A enzyme, heterozygous variants at Arg882 exert a dominant-negative effect by inactivating wild type DNMT3A [Russler-Germain et al 2014]. Variants affecting Arg882 have been shown to cause more significant hypomethylation than other variants, which may explain why they are more frequently observed in individuals with sporadic malignancy [Smith et al 2021].

For individuals with TBRS who have psychiatric issues, it has been suggested that abnormal catalytic function of the methyltransferase domain could affect metabolic pathways in the brain [Tenorio et al 2020], but further work, including longitudinal observation of individuals with TBRS progressing into adulthood, is required to confirm whether this is a robust genotype-phenotype association.

Mechanism of disease causation. The mechanism of disease is loss of function. The common pathogenic variants at Arg882 (R882), which are associated with both TBRS and sporadic acute myeloid leukemia, may exert an additional dominant-negative effect.

DNMT3A-specific laboratory technical considerations. Somatic variants in DNMT3A are associated with clonal hematopoiesis and sporadic hematologic malignancies [Ley et al 2010, Jaiswal et al 2014], suggesting that they may be enriched in population databases derived from peripheral blood samples. This has significant implications for variant interpretation, and caution is advised when assessing population frequencies. In particular, the presence of a variant in population databases does not necessarily provide evidence against pathogenicity, as its occurrence in the general population may represent somatic rather than germline variation.

Cancer and Benign Tumors

DNMT3A is a known driver of clonal hematopoiesis [Jaiswal et al 2014] and hematologic malignancy in the general population, with somatic pathogenic variants present in more than 20% of individuals with sporadic acute myeloid leukemia (AML) [Ley et al 2010]. The Arg882 (R882) residue is affected in more than 50% of these cases [Ley et al 2010]. DNMT3A variants are an independent predictor of poor prognosis in AML [Ley et al 2010, Papaemmanuil et al 2016]. There is evidence that mutation of DNMT3A is an early event in clonal hematopoiesis, which predisposes to malignancy but is not in itself sufficient to lead to malignancy [Papaemmanuil et al 2016].

Author Notes

Professor Kate Tatton-Brown is a medical geneticist. She runs a research study to investigate the genetic causes and clinical presentations of conditions associated with increased growth and learning disability. The research study is funded by the Baily Thomas Charitable fund and the St George's Charity.

Dr Philip Ostrowski is a clinical genetics registrar at St George's Hospital and Great Ormond Street Hospital in London. He has a special interest in cardiovascular genetics, and has published case series describing the overgrowth phenotypes associated with pathogenic variants in CHD8 and BRWD3, jointly with Professor Tatton-Brown.

Acknowledgments

The authors would like to thank the individuals with Tatton-Brown-Rahman syndrome and their families, who have taught us a lot about this syndrome. We would also like to thank the clinician collaborator teams of physicians, genetic counselors, nurses, therapists and allied professionals, and trainees who have generously cared for these patients and supported efforts to gather information to clarify features and optimize care for patients and families.

Revision History

• 30 June 2022 (ma) Review posted live
• 31 January 2022 (ktb) Original submission

Literature Cited

• Balci TB, Strong A, Kalish JM, Zackai E, Maris JM, Reilly A, Surrey LF, Wertheim GB, Marcadier JL, Graham GE, Carter MT. Tatton-Brown-Rahman syndrome: six individuals with novel features. Am J Med Genet A. 2020;182:673-80. [PubMed: 31961069]
• Cecchi AC, Haidar A, Marin I, Kwartler CS, Prakash SK, Milewicz DM. Aortic root dilatation and dilated cardiomyopathy in an adult with Tatton-Brown-Rahman syndrome. Am J Med Genet A. 2022;188:628-34. [PMC free article: PMC9175539] [PubMed: 34644003]
• Ferris MA, Smith AM, Heath SE, Duncavage EJ, Oberley M, Freyer D, Wynn R, Douzgou S, Maris JM, Reilly AF, Wu MD, Choo F, Fiets RB, Koene S, Spencer DH, Miller CA, Shinawi M, Ley TJ. DNMT3A overgrowth syndrome is associated with the development of hematopoietic malignancies in children and young adults. Blood. 2022;139:461-4. [PMC free article: PMC8777205] [PubMed: 34788385]
• Hage C, Sabini E, Alsharhan H, Fahrner JA, Beckers A, Daly A, Salvatori R. Acromegaly in the setting of Tatton-Brown-Rahman Syndrome. Pituitary. 2020;23:167-70. [PubMed: 31858400]
• Heyn P, Logan CV, Fluteau A, Challis RC, Auchynnikava T, Martin CA, Marsh JA, Taglini F, Kilanowski F, Parry DA, Cormier-Daire V, Fong CT, Gibson K, Hwa V, Ibáñez L, Robertson SP, Sebastiani G, Rappsilber J, Allshire RC, Reijns MAM, Dauber A, Sproul D, Jackson AP. Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. Nat Genet. 2019;51:96-105. [PMC free article: PMC6520989] [PubMed: 30478443]
• Hollink IHIM, van den Ouweland AMW, Beverloo HB, Arentsen-Peters STCJM, Zwaan CM, Wagner A. Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation. J Med Genet. 2017;54:805-8. [PubMed: 28432085]
• Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, Higgins JM, Moltchanov V, Kuo FC, Kluk MJ, Henderson B, Kinnunen L, Koistinen HA, Ladenvall C, Getz G, Correa A, Banahan BF, Gabriel S, Kathiresan S, Stringham HM, McCarthy MI, Boehnke M, Tuomilehto J, Haiman C, Groop L, Atzmon G, Wilson JG, Neuberg D, Altshuler D, Ebert BL. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488-98. [PMC free article: PMC4306669] [PubMed: 25426837]
• Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, Sasaki H. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature. 2004;429:900-3. [PubMed: 15215868]
• Kosaki R, Terashima H, Kubota M, Kosaki K. Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation. Am J Med Genet A. 2017;173:250-3. [PubMed: 27991732]
• Lane C, Tatton-Brown K, Freeth M. Tatton-Brown-Rahman syndrome: cognitive and behavioural phenotypes. Dev Med Child Neurol. 2020;62:993-8. [PubMed: 31845314]
• 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;173:1887-90. [PubMed: 28449304]
• Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O'Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, Swift GW, Reed JP, Alldredge PA, Wylie T, Walker J, Kalicki J, Watson MA, Heath S, Shannon WD, Varghese N, Nagarajan R, Westervelt P, Tomasson MH, Link DC, Graubert TA, DiPersio JF, Mardis ER, Wilson RK. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424-33. [PMC free article: PMC3201818] [PubMed: 21067377]
• Okamoto N, Toribe Y, Shimojima K, Yamamoto T. Tatton-Brown-Rahman syndrome due to 2p23 microdeletion. Am J Med Genet A. 2016;170A:1339-42. [PubMed: 26866722]
• Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247-57. [PubMed: 10555141]
• Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, Potter NE, Heuser M, Thol F, Bolli N, Gundem G, Van Loo P, Martincorena I, Ganly P, Mudie L, McLaren S, O'Meara S, Raine K, Jones DR, Teague JW, Butler AP, Greaves MF, Ganser A, Döhner K, Schlenk RF, Döhner H, Campbell PJ. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209-21. [PMC free article: PMC4979995] [PubMed: 27276561]
• Paz-Alegría MC, Gómez-Forero D, Osorio-Patiño J, Jaramillo-Echeverry A. Behavioral and dental management of a patient with Tatton-Brown-Rahman syndrome: case report. Spec Care Dentist. 2020;40:597-604. [PubMed: 32815590]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Russler-Germain DA, Spencer DH, Young MA, Lamprecht TL, Miller CA, Fulton R, Meyer MR, Erdmann-Gilmore P, Townsend RR, Wilson RK, Ley TJ. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell. 2014;25:442-54. [PMC free article: PMC4018976] [PubMed: 24656771]
• Shen W, Heeley JM, Carlston CM, Acuna-Hidalgo R, Nillesen WM, Dent KM, Douglas GV, Levine KL, Bayrak-Toydemir P, Marcelis CL, Shinawi M, Carey JC. The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies. Am J Med Genet A. 2017;173:3022-8. [PubMed: 28941052]
• Smith AM, LaValle TA, Shinawi M, Ramakrishnan SM, Abel HJ, Hill CA, Kirkland NM, Rettig MP, Helton NM, Heath SE, Ferraro F, Chen DY, Adak S, Semenkovich CF, Christian DL, Martin JR, Gabel HW, Miller CA, Ley TJ. Functional and epigenetic phenotypes of humans and mice with DNMT3A overgrowth syndrome. Nat Commun. 2021;12:4549. [PMC free article: PMC8316576] [PubMed: 34315901]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Sweeney KJ, Mottolese C, Belot A, Szathmari A, Frappaz D, Lesca G, Putoux A, Di Rocco F. The first case report of medulloblastoma associated with Tatton-Brown-Rahman syndrome. Am J Med Genet A. 2019;179:1357-61. [PubMed: 31066180]
• Tatton-Brown K, Loveday C, Yost S, Clarke M, Ramsay E, Zachariou A, Elliott A, Wylie H, Ardissone A, Rittinger O, Stewart F, Temple IK, Cole T, Mahamdallie S, Seal S, Ruark E, Rahman N, et al. Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability. Am J Hum Genet. 2017;100:725-36. [PMC free article: PMC5420355] [PubMed: 28475857]
• 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, van Montfort R, Rahman N, et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014;46:385-8. [PMC free article: PMC3981653] [PubMed: 24614070]
• Tatton-Brown K, Zachariou A, Loveday C, Renwick A, Mahamdallie S, Aksglaede L, Baralle D, Barge-Schaapveld D, Blyth M, Bouma M, Breckpot J, Crabb B, Dabir T, Cormier-Daire V, Fauth C, Fisher R, Gener B, Goudie D, Homfray T, Hunter M, Jorgensen A, Kant SG, Kirally-Borri C, Koolen D, Kumar A, Labilloy A, Lees M, Marcelis C, Mercer C, Mignot C, Miller K, Neas K, Newbury-Ecob R, Pilz DT, Posmyk R, Prada C, Ramsey K, Randolph LM, Selicorni A, Shears D, Suri M, Temple IK, Turnpenny P, Val Maldergem L, Varghese V, Veenstra-Knol HE, Yachelevich N, Yates L, Rahman N, et al. The Tatton-Brown-Rahman syndrome: a clinical study of 55 individuals with de novo constitutive DNMT3A variants. Wellcome Open Res. 2018;3:46. [PMC free article: PMC5964628] [PubMed: 29900417]
• Tenorio J, Alarcón P, Arias P, Dapía I, García-Miñaur S, Palomares Bralo M, Campistol J, Climent S, Valenzuela I, Ramos S, Monseny AM, Grondona FL, Botet J, Serrano M, Solís M, Santos-Simarro F, Álvarez S, Teixidó-Tura G, Fernández Jaén A, Gordo G, Bardón Rivera MB, Nevado J, Hernández A, Cigudosa JC, Ruiz-Pérez VL, Tizzano EF, Lapunzina P, et al. Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients. Eur J Hum Genet. 2020;28:469-79. [PMC free article: PMC7080728] [PubMed: 31685998]
• Tlemsani C, Luscan A, Leulliot N, Bieth E, Afenjar A, Baujat G, Doco-Fenzy M, Goldenberg A, Lacombe D, Lambert L, Odent S, Pasche J, Sigaudy S, Buffet A, Violle-Poirsier C, Briand-Suleau A, Laurendeau I, Chin M, Saugier-Veber P, Vidaud D, Cormier-Daire V, Vidaud M, Pasmant E, Burglen L. SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. J Med Genet. 2016;53:743-51. [PubMed: 27317772]
• 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;91:623-8. [PubMed: 27701732]
• Yokoi T, Enomoto Y, Naruto T, Kurosawa K, Higurashi N. Tatton-Brown-Rahman syndrome with a novel DNMT3A mutation presented severe intellectual disability and autism spectrum disorder. Hum Genome Var. 2020;7:15. [PMC free article: PMC7235239] [PubMed: 32435502]