The spectrum of <i>DNMT3A</i> variants in Tatton–Brown–Rahman syndrome overlaps with that in hematologic malignancies

Shen, Wei; Heeley, Jennifer; Carlston, Colleen M.; Acuña-Hidalgo, Rocío; Nillesen, Willy M.; Dent, Karin M.; Douglas, Ganka; Levine, Kara L.; Bayrak-Toydemir, Pınar; Marcelis, Carlo; Shinawi, Marwan; Carey, John C.

doi:10.1002/ajmg.a.38485

Cited by 44 publications

(36 citation statements)

References 29 publications

(41 reference statements)

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“…To date, 78 individuals have been described with the overgrowth condition TBRS. Within this group, a wide variety of germline DNMT3A pathogenic variants have been reported, including 33 missense, eight stop-gain, seven frameshift and two splice site variants, two in-frame and five whole-gene deletions (including a set of identical twins) (Tatton-Brown et al 2014;Okamoto et al 2016;Tlemsani et al 2016;Hollink et al 2017;Kosaki et al 2017;Lemire et al 2017;Shen et al 2017;Spencer et al 2017;Tatton-Brown et al 2017Xin et al 2017 The majority of DNMT3A pathogenic variants in TBRS have been found to be de novo, with five individuals inheriting the pathogenic variant from two mosaic parents (Tlemsani et al 2016;Xin et al 2017) and two individuals inheriting the pathogenic variant from their affected father (Lemire et al 2017). Extensive studies of the role of DNMT3A in hematopoietic stem cell (HSC) differentiation are also reported, including the regular occurrence of somatic DNMT3A variants in patients with acute myeloid leukemia (AML).…”

Section: Discussionmentioning

confidence: 99%

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

et al. 2019

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Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown–Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.

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Section: Discussionmentioning

confidence: 99%

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

et al. 2019

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“…The most common somatic pathogenic variant reported in patients with AML affects the amino acid residue Arg882. To date, pathogenic variation at this residue has been described in the germline of 12 TBRS patients, five with p.(Arg882His) and seven with p.(Arg882Cys) (Tlemsani et al 2016;Hollink et al 2017;Kosaki et al 2017;Shen et al 2017;Spencer et al 2017;Tatton-Brown et al 2018). Despite 1 9…”

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confidence: 99%

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

Jeffries

Maroofian

Salter

et al. 2018

Preprint

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Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3A (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G>A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated to genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. Notably, these findings were most striking in a carrier of the AML associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders; NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamentally new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance and determinants of biological aging in these growth disorders.

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“…Central apnea was observed to persist beyond the neonatal period in two of our patients (P4 and P5, Table 1). We provide additional phenotyping of central sleep apnea that has been previously reported in TBRS (Shen et al, 2017;Tatton-Brown et al, 2018).…”

Section: Discussionmentioning

confidence: 95%

“…Arg882 is within the catalytic domain of the protein and a recurrent somatic hotspot in AML (Hollink et al, 2017). Germline variants at this residue have been described recurrently in TBRS patients (Hollink et al, 2017;Kosaki et al, 2017;Shen et al, 2017;Tatton-Brown et al, 2018;Tlemsani et al, 2016). In our six-patient series, we had two patients with variants at Arg882, bringing the total number of individuals with variants in this residue to 13 (out of 84, 15.5%).…”

Section: Discussionmentioning

confidence: 99%

“…At the time of writing, 78 individuals with TBRS have been reported, with an age range of 1.5 to 54 years, including 21 adults and one family with autosomal dominant transmission (Hollink et al, 2017;Kosaki, Terashima, Kubota, & Kosaki, 2017;Lemire, Gauthier, Soucy, & Delrue, 2017;Okamoto, Toribe, Shimojima, & Yamamoto, 2016;Shen et al, 2017;Sweeney et al, 2019;Tatton-Brown et al, 2018;Tlemsani et al, 2016;Xin et al, 2017). All probands share a consistent phenotype of overgrowth, intellectual disability, and dysmorphic features including long or round face, horizontal and laterally (Hollink et al, 2017;Tatton-Brown et al, 2018) and more recently, medulloblastoma was described in one individual (Sweeney et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Tatton‐Brown‐Rahman syndrome: Six individuals with novel features

Balci

Strong

Kalish

et al. 2020

American J of Med Genetics Pt A

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Tatton‐Brown Rahman syndrome (TBRS) is an overgrowth‐intellectual disability syndrome caused by heterozygous variants in DNMT3A. Seventy‐eight individuals have been reported with a consistent phenotype of somatic overgrowth, mild to moderate intellectual disability, and similar dysmorphisms. We present six individuals with TBRS, including the youngest individual thus far reported, first individual to be diagnosed with tumor testing and two individuals with variants at the Arg882 domain, bringing the total number of reported cases to 82. Patients reported herein have additional clinical features not previously reported in TBRS. One patient had congenital diaphragmatic hernia. One patient carrying the recurrent p.Arg882His DNMT3A variant, who was previously reported as having a phenotype due to a truncating variant in the CLTC gene, developed a ganglioneuroblastoma at 18 months and T‐cell lymphoblastic lymphoma at 6 years of age. Four patients manifested symptoms suggestive of autonomic dysfunction, including central sleep apnea, postural orthostatic hypotension, and episodic vasomotor instability in the extremities. We discuss the molecular and clinical findings in our patients with TBRS in context of existing literature.

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The spectrum of DNMT3A variants in Tatton–Brown–Rahman syndrome overlaps with that in hematologic malignancies

Cited by 44 publications

References 29 publications

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging

Tatton‐Brown‐Rahman syndrome: Six individuals with novel features

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