Co-occurrence of a maternally inherited DNMT3A duplication and a paternally inherited pathogenic variant in EZH2 in a child with growth retardation and severe short stature: atypical Weaver syndrome or evidence of a DNMT3A dosage effect?

Katarzyna Polonis, Patrick R. Blackburn, Raul A. Urrutia, Gwen A. Lomberk, Teresa Kruisselbrink, Margot A. Cousin, Nicole J. Boczek, Nicole L. Hoppman, Dusica Babovic-Vuksanovic, Eric W Klee, Pavel N. Pichurin

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Overgrowth syndromes are a clinically heterogeneous group of disorders characterized by localized or generalized tissue overgrowth and varying degrees of developmental and intellectual disability. An expanding list of genes associated with overgrowth syndromes include the histone methyltransferase genes EZH2 and NSD1, which cause Weaver and Sotos syndrome, respectively, and the DNA methyltransferase (DNMT3A) gene that results in Tatton-Brown-Rahman syndrome (TBRS). Here, we describe a 5-year-old female with a paternally inherited pathogenic mutation in EZH2 (c.2050C>T, p.Arg684Cys) and a maternally inherited 505-kb duplication of uncertain significance at 2p23.3 (encompassing five genes, including DNMT3A) who presented with intrauterine growth restriction, slow postnatal growth, short stature, hypotonia, developmental delay, and neuroblastoma diagnosed at the age of 8 mo. Her father had tall stature, dysmorphic facial features, and intellectual disability consistent with Weaver syndrome, whereas her mother had short stature, cognitive delays, and chronic nonprogressive leukocytosis. It has been previously shown that EZH2 directly controls DNA methylation through physical association with DNMTs, including DNMT3A, with concomitant H3K27 methylation and CpG promoter methylation leading to repression of EZH2 target genes. Interestingly, NSD1 is involved in H3K36 methylation, a mark associated with transcriptional activation, and exhibits exquisite dosage sensitivity leading to overgrowth when deleted and severe undergrowth when duplicated in vivo. Although there is currently no evidence of dosage effects for DNMT3A, the co-occurrence of a duplication involving this gene and a pathogenic alteration in EZH2 in a patient with severe undergrowth is suggestive of a similar paradigm and further study is warranted.

Original languageEnglish (US)
JournalCold Spring Harbor molecular case studies
Volume4
Issue number4
DOIs
StatePublished - Aug 1 2018

Fingerprint

Methylation
Growth
Genes
Intellectual Disability
Sotos Syndrome
Developmental Disabilities
Muscle Hypotonia
Gene Duplication
Leukocytosis
Methyltransferases
DNA Methylation
Neuroblastoma
Fathers
Transcriptional Activation
Mothers
Maternal Inheritance
Weaver syndrome
Paternal Inheritance
Mutation
DNA

Keywords

  • bilateral talipes equinovarus
  • delayed gross motor development
  • generalized neonatal hypotonia
  • hip dysplasia
  • microretrognathia
  • moderate expressive language delay
  • moderate global developmental delay
  • moderate intrauterine growth retardation
  • neuroblastoma
  • overgrowth
  • short stature

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Co-occurrence of a maternally inherited DNMT3A duplication and a paternally inherited pathogenic variant in EZH2 in a child with growth retardation and severe short stature : atypical Weaver syndrome or evidence of a DNMT3A dosage effect? / Polonis, Katarzyna; Blackburn, Patrick R.; Urrutia, Raul A.; Lomberk, Gwen A.; Kruisselbrink, Teresa; Cousin, Margot A.; Boczek, Nicole J.; Hoppman, Nicole L.; Babovic-Vuksanovic, Dusica; Klee, Eric W; Pichurin, Pavel N.

In: Cold Spring Harbor molecular case studies, Vol. 4, No. 4, 01.08.2018.

Research output: Contribution to journalArticle

Polonis, Katarzyna ; Blackburn, Patrick R. ; Urrutia, Raul A. ; Lomberk, Gwen A. ; Kruisselbrink, Teresa ; Cousin, Margot A. ; Boczek, Nicole J. ; Hoppman, Nicole L. ; Babovic-Vuksanovic, Dusica ; Klee, Eric W ; Pichurin, Pavel N. / Co-occurrence of a maternally inherited DNMT3A duplication and a paternally inherited pathogenic variant in EZH2 in a child with growth retardation and severe short stature : atypical Weaver syndrome or evidence of a DNMT3A dosage effect?. In: Cold Spring Harbor molecular case studies. 2018 ; Vol. 4, No. 4.
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abstract = "Overgrowth syndromes are a clinically heterogeneous group of disorders characterized by localized or generalized tissue overgrowth and varying degrees of developmental and intellectual disability. An expanding list of genes associated with overgrowth syndromes include the histone methyltransferase genes EZH2 and NSD1, which cause Weaver and Sotos syndrome, respectively, and the DNA methyltransferase (DNMT3A) gene that results in Tatton-Brown-Rahman syndrome (TBRS). Here, we describe a 5-year-old female with a paternally inherited pathogenic mutation in EZH2 (c.2050C>T, p.Arg684Cys) and a maternally inherited 505-kb duplication of uncertain significance at 2p23.3 (encompassing five genes, including DNMT3A) who presented with intrauterine growth restriction, slow postnatal growth, short stature, hypotonia, developmental delay, and neuroblastoma diagnosed at the age of 8 mo. Her father had tall stature, dysmorphic facial features, and intellectual disability consistent with Weaver syndrome, whereas her mother had short stature, cognitive delays, and chronic nonprogressive leukocytosis. It has been previously shown that EZH2 directly controls DNA methylation through physical association with DNMTs, including DNMT3A, with concomitant H3K27 methylation and CpG promoter methylation leading to repression of EZH2 target genes. Interestingly, NSD1 is involved in H3K36 methylation, a mark associated with transcriptional activation, and exhibits exquisite dosage sensitivity leading to overgrowth when deleted and severe undergrowth when duplicated in vivo. Although there is currently no evidence of dosage effects for DNMT3A, the co-occurrence of a duplication involving this gene and a pathogenic alteration in EZH2 in a patient with severe undergrowth is suggestive of a similar paradigm and further study is warranted.",
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AU - Blackburn, Patrick R.

AU - Urrutia, Raul A.

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AU - Kruisselbrink, Teresa

AU - Cousin, Margot A.

AU - Boczek, Nicole J.

AU - Hoppman, Nicole L.

AU - Babovic-Vuksanovic, Dusica

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KW - neuroblastoma

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