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?

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.

Sequenced-based GWAS for linear classification traits in Belgian Blue beef cattle reveals new coding variants in genes regulating body size in mammals

“…In agreement, ADAM12 -deficient zebrafish present growth retardation [ 66 ]. In humans, mutations in EZH2 cause the Weaver syndrome and increased height [ 67 ], tall stature [ 68 ] but also growth retardation and severe short stature [ 69 ]. Two of these coding variants were the lead variants in their respective MT-GWAS.…”

PRC2 functions in development and congenital disorders

“…For example, whereas NSD1 haploinsufficiency is associated with overgrowth, reciprocal duplications involving NSD1 correlate with opposing clinical features, including growth retardation, delayed bone age and microcephaly (Dikow et al, 2013; Rosenfeld et al, 2013). Similarly, an individual with a maternally inherited duplication encompassing DNMT3A exhibits a growth failure phenotype marked by developmental delay, despite also possessing a paternally inherited Weaver syndrome-related point mutation in EZH2 (Polonis et al, 2018). This phenotype suggests that the increased gene dosage of DNMT3A exerts dominant effects that serve to restrict growth, masking any contribution from the missense EZH2 mutation, which normally causes overgrowth.…”

Sequenced-based GWAS for linear classification traits in Belgian Blue beef cattle reveals new coding variants in genes regulating body size in mammals

“…In agreement, ADAM12-deficient zebrafish present growth retardation [59]. In human, mutations in EZH2 cause the Weaver syndrome and increased height [60], tall stature [61] but also growth retardation and severe short stature [62]. Two of these coding variants were the lead variants in their respective MT-GWAS.…”