Abstract
DNA methylation plays a critical role in both embryonic development and tumorigenesis and is mediated through various DNA methyltransferases. Constitutional mutations in the de novo DNA methyltransferase DNMT3A cause a recently identified Tatton-Brown–Rahman overgrowth syndrome (TBRS). Somatically acquired mutations in DNMT3A are causally associated with acute myeloid leukemia (AML), and p.Arg882His represents the most prevalent hotspot. So far, no patients with TBRS have been reported to have subsequently developed AML. Here, we report a live birth and the survival of a female with the TBRS phenotype who had a heterozygous constitutional DNMT3A mutation at the AML somatic mutation hotspot p.Arg882His in her DNA from peripheral blood and buccal tissue. Her characteristic features at birth included hypotonia, narrow palpebral fissures, ventricular septal defect, umbilical hernia, sacral cyst, Chiari type I anomaly. At the age of 6 years, she exhibited overgrowth (> 3 SD) and round face and intellectual disability. This report represents the first documentation of the same variant (DNMT3A p.Arg882His) as both the constitutional mutation associated with TBRS and the somatic mutation hotspot of AML. The observation neither confirms nor denies the notion that mutations responsible for TBRS and those for AML might share the same mode of action. Larger data sets are required to determine whether TBRS patients with constitutional DNMT3A mutations are at an increased risk for AML.
| Original language | English |
|---|---|
| Pages (from-to) | 250-253 |
| Number of pages | 4 |
| Journal | American Journal of Medical Genetics, Part A |
| Volume | 173 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2017 Jan 1 |
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Keywords
- acute myeloid leukemia
- AML
- DNMT3A
- overgrowth
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown–Rahman overgrowth syndrome as a constitutional mutation. / Kosaki, Rika; Terashima, Hiroshi; Kubota, Masaya; Kosaki, Kenjiro.
In: American Journal of Medical Genetics, Part A, Vol. 173, No. 1, 01.01.2017, p. 250-253.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown–Rahman overgrowth syndrome as a constitutional mutation
AU - Kosaki, Rika
AU - Terashima, Hiroshi
AU - Kubota, Masaya
AU - Kosaki, Kenjiro
PY - 2017/1/1
Y1 - 2017/1/1
N2 - DNA methylation plays a critical role in both embryonic development and tumorigenesis and is mediated through various DNA methyltransferases. Constitutional mutations in the de novo DNA methyltransferase DNMT3A cause a recently identified Tatton-Brown–Rahman overgrowth syndrome (TBRS). Somatically acquired mutations in DNMT3A are causally associated with acute myeloid leukemia (AML), and p.Arg882His represents the most prevalent hotspot. So far, no patients with TBRS have been reported to have subsequently developed AML. Here, we report a live birth and the survival of a female with the TBRS phenotype who had a heterozygous constitutional DNMT3A mutation at the AML somatic mutation hotspot p.Arg882His in her DNA from peripheral blood and buccal tissue. Her characteristic features at birth included hypotonia, narrow palpebral fissures, ventricular septal defect, umbilical hernia, sacral cyst, Chiari type I anomaly. At the age of 6 years, she exhibited overgrowth (> 3 SD) and round face and intellectual disability. This report represents the first documentation of the same variant (DNMT3A p.Arg882His) as both the constitutional mutation associated with TBRS and the somatic mutation hotspot of AML. The observation neither confirms nor denies the notion that mutations responsible for TBRS and those for AML might share the same mode of action. Larger data sets are required to determine whether TBRS patients with constitutional DNMT3A mutations are at an increased risk for AML.
AB - DNA methylation plays a critical role in both embryonic development and tumorigenesis and is mediated through various DNA methyltransferases. Constitutional mutations in the de novo DNA methyltransferase DNMT3A cause a recently identified Tatton-Brown–Rahman overgrowth syndrome (TBRS). Somatically acquired mutations in DNMT3A are causally associated with acute myeloid leukemia (AML), and p.Arg882His represents the most prevalent hotspot. So far, no patients with TBRS have been reported to have subsequently developed AML. Here, we report a live birth and the survival of a female with the TBRS phenotype who had a heterozygous constitutional DNMT3A mutation at the AML somatic mutation hotspot p.Arg882His in her DNA from peripheral blood and buccal tissue. Her characteristic features at birth included hypotonia, narrow palpebral fissures, ventricular septal defect, umbilical hernia, sacral cyst, Chiari type I anomaly. At the age of 6 years, she exhibited overgrowth (> 3 SD) and round face and intellectual disability. This report represents the first documentation of the same variant (DNMT3A p.Arg882His) as both the constitutional mutation associated with TBRS and the somatic mutation hotspot of AML. The observation neither confirms nor denies the notion that mutations responsible for TBRS and those for AML might share the same mode of action. Larger data sets are required to determine whether TBRS patients with constitutional DNMT3A mutations are at an increased risk for AML.
KW - acute myeloid leukemia
KW - AML
KW - DNMT3A
KW - overgrowth
UR - http://www.scopus.com/inward/record.url?scp=84997794990&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84997794990&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.37995
DO - 10.1002/ajmg.a.37995
M3 - Article
C2 - 27991732
AN - SCOPUS:84997794990
VL - 173
SP - 250
EP - 253
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
IS - 1
ER -