Weaver Syndrome

Last update 08 May 2025

Basic Info

Synonyms

Camptodactyly-overgrowth-unusual facies syndrome, Marshall-Smith-Weaver syndrome, WEAVER SYNDROME

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Introduction

A rare syndrome caused by mutations in the EZH2 gene, and rarely mutations in the NSD1 gene. It is characterized by advanced bone age, foot deformities, permanently bent joints, macrocephaly, flattened back of the head, a broad forehead, hypertelorism, large, low-set ears, micrognathia, delayed development of motor skills, and mild intellectual disability.

100 Clinical Results associated with Weaver Syndrome

100 Translational Medicine associated with Weaver Syndrome

0 Patents (Medical) associated with Weaver Syndrome

226

Literatures (Medical) associated with Weaver Syndrome

01 Mar 2025·Human Gene Therapy

Minimally Humanized Ezh2 Exon-18 Mouse Cell Lines Validate Preclinical CRISPR/Cas9 Approach to Treat Weaver Syndrome

Article

Author: Gibson, William T. ; Adair, Bethany A. ; Janssen, Sanne M. ; Gamu, Daniel ; Lengyell, Tess C. ; Korecki, Andrea J. ; Simpson, Elizabeth M. ; Lorincz, Matthew C.

Weaver syndrome is a rare neurodevelopmental disorder that encompasses macrocephaly, tall stature, obesity, brain anomalies, intellectual disability, and increased susceptibility to cancer. This dominant monogenic disorder is caused by germline variants in enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), a key epigenetic writer. Unfortunately, there are no effective treatments for Weaver syndrome. However, preclinical results support the potential for therapeutic gains, despite the prenatal onset. Thus, for the first time, we tested whether CRISPR/Cas9 gene-editing strategies may be able to "correct" a Weaver syndrome variant at the DNA level. We initiated these preclinical studies by humanizing the region surrounding the most-common recurring patient-variant location in mouse embryonic stem cells (ESCs). Humanization ensures that DNA-binding strategies will be directly translatable to human cells and patients. We then introduced into ESCs the humanized region, but now carrying the Weaver syndrome EZH2 variant c.2035C>T p.Arg684Cys, and characterized the enzymatic properties of this missense variant. Our data showed a significant and dramatic reduction in EZH2-enzymatic activity, supporting previous cell-free studies of this variant as well as in vitro and in vivo mouse work by other teams. Intriguingly, this most-common variant does not create a complete loss-of-function, but rather is a hypomorphic allele. Together with prior reports describing hypomorphic effects of missense EZH2 variants, these results demonstrate that the etiology of Weaver syndrome does not require complete loss of EZH2 enzymatic activity. Toward therapy, we tested four CRISPR gene-editing strategies. We demonstrated that Streptococcus pyogenes Cas9 (SpCas9) showed the highest variant correction (70.5%), but unfortunately also the highest alteration of the nonvariant allele (21.1-26.2%), an important consideration for gene-editing treatment of a dominant syndrome. However, Staphylococcus aureus Cas9 (SaCas9) gave a variant correction (52.5%) that was not significantly different than SpCas9, and encouragingly the lowest alteration of the nonvariant allele (2.0%). Thus, the therapeutic strategy using the small SaCas9 enzyme, a size that allows flexibility in therapeutic delivery, was the most optimal for targeting the Weaver syndrome EZH2 variant c.2035C>T p.Arg684Cys.

01 Oct 2024·American Journal of Medical Genetics Part A

Biallelic loss‐of‐function variants of EZH1 cause a novel developmental disorder with central precocious puberty

Article

Author: Yanagi, Kumiko ; Okamoto, Nobuhiko ; Kaname, Tadashi ; Ogitani, Ayako ; Yoshida, Sayaka ; Etani, Yuri

AbstractPathogenic variants of polycomb repressive complex‐2 (PRC2) subunits are associated with overgrowth syndromes and neurological diseases. EZH2 is a major component of PRC2 and mediates the methylation of H3K27 trimethylation (H3K27me3). Germline variants of EZH2 have been identified as a cause of Weaver syndrome (WS), an overgrowth/intellectual disability (OGID) syndrome characterized by overgrowth, macrocephaly, accelerated bone age, intellectual disability (ID), and characteristic facial features. Germline variants of SUZ12 and EED, other components of PRC2, have also been reported in the WS or Weaver‐like syndrome. EZH1 is a homolog of EZH2 that interchangeably associates with SUZ12 and EED. Recently, pathogenic variants of EZH1 have been reported in individuals with dominant and recessive neurodevelopmental disorders. We herein present sisters with biallelic loss‐of‐function variants of EZH1. They showed developmental delay, ID, and central precocious puberty, but not the features of WS or other OGID syndromes.

01 Oct 2024·PM&R

Delayed diagnosis of cervical myelopathy in an adult with Weaver syndrome

Letter

Author: Manocha, Ranita Harpreet Kaur ; Yao, Yvette Ysabel

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Weaver Syndrome

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