The phenotype of EZH2 haploinsufficiency—1.2‐Mb deletion at 7q36.1 in a child with tall stature and intellectual disability

Abstract

Weaver syndrome is a rare overgrowth syndrome with distinct facial features in young children and variable learning disability. Heterozygous missense mutations in EZH2 are present in over 90% of patients with Weaver syndrome but the exact mechanism by which EZH2 mutations cause Weaver syndrome is unknown. We report an 11-year-old boy with a de novo 1.2-Mb deletion at 7q36.1 including EZH2 who has tall stature, significant intellectual disability, and some physical features of Weaver syndrome. Emerging evidence in the literature indicates that Weaver syndrome EZH2 mutations may result in loss of function of the gene and our report suggests that haploinsufficiency of EZH2 may replicate the clinical phenotype of Weaver syndrome.

PRC2 functions in development and congenital disorders

“…Although simple haploinsufficiency is not thought to be the mutational mechanism underlying Weaver syndrome, there is a report of an individual who is haploinsufficient for EZH2 and exhibits some of the features of Weaver syndrome, including overgrowth and intellectual disability (Suri and Dixit, 2017). The overgrowth-associated pathogenic variants of EZH2 , EED and SUZ12 have, to date, been predicted to be caused by predominantly loss-of-function mutations (Cohen et al, 2016; Imagawa et al, 2017; Lui et al, 2018; Spellicy et al, 2019; Tatton-Brown et al, 2013).…”

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?

“…Interestingly, there is some emerging evidence suggesting that EZH2 and DNMT3A may exhibit dosage sensitivity as well. A recent report of an individual with suspected overgrowth and a 1.2-Mb deletion involving EZH2 and several other genes supports haploinsufficiency as the underlying disease mechanism in Weaver syndrome ( Suri and Dixit 2017 ). Similarly, 2p23 microdeletions involving DNMT3A have been observed in individuals with phenotypes consistent with TBRS, suggesting that haploinsufficiency of this gene could also result in overgrowth ( Shoukier et al 2012 ; Bloch et al 2014 ; Okamoto et al 2016 ).…”

Two new cases of interstitial 7q35q36.1 deletion including CNTNAP2 and KMT2C

“…Among these genes, CNTNAP2 , EZH2 , KCNH2 , NOS3 , CDK5 , ASB10 , PRKAG2 , KMT2C , and XRCC2 genes were associated with an OMIM phenotype (Table S1 ). Through a systematic review of patients carrying a pure heterozygous 7q deletion which boundaries were included in those of our patients, we identified three patients in literature reports (Friedman et al, 2008 ; Smogavec et al, 2016 ; Suri & Dixit, 2017 ), including one case with two intragenic deletions in CNTNAP2 gene an, four cases in the DECIPHER database ( https://decipher.sanger.ac.uk ). The clinical and the molecular data from nine patients (two from this study and seven previously reported) carrying a 7q35 and/or 7q36.1 deletion are summarized in Table 1 and Figure 3 .…”

“…Point mutation and deletion on KCNH2 are pathogenic (Huang et al, 2010 ). Other patients harboring a 7q deletion encompassing KCNH2 were found to have a long QT syndrome (Ayub et al, 2016 ; Di Stolfo et al, 2019 ; Suri & Dixit, 2017 ). Thus, cardiac monitoring should be implemented in the patients with a defect of these genes.…”

“…However, the report of interstitial deletion that does not implicate the SHH region is missing. Indeed, deletions affecting a more proximal part, namely, bands 7q35q36.1, are less common (Fagan et al, 1994 ; Friedman et al, 2008 ; Smogavec et al, 2016 ; Suri & Dixit, 2017 ). We report two patients with a 4.4‐Mb interstitial deletion in 7q36.1 and a 4.8‐Mb interstitial deletion in 7q35q36.1 detected by array‐comparative genomic hybridization.…”