Novel de novo mutation affecting two adjacent aminoacids in the EED gene in a patient with Weaver syndrome

Śmigiel, Robert; Biernacka, Anna; Biela, Mateusz; Pienkowski, Victor Murcia; Szmida, Elżbieta; Gasperowicz, Piotr; Kosińska, Joanna; Kostrzewa, Grażyna; Koppolu, Agnieszka; Walczak, Anna; Wawrzuta, Dominik; Rydzanicz, Małgorzata; Sasiadek, Maria M.; Płoski, Rafał

doi:10.1038/s10038-017-0391-x

Cited by 16 publications

(31 citation statements)

References 7 publications

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“…Constitutive EZH2 variants cause Weaver syndrome (MIM 277590), an OGID syndrome characterized by tall stature, a variable intellectual disability and recognizable facial features including a broad forehead, hypertelorism, almond‐shaped palpebral fissures, a pointed “stuck‐on” chin, large ears, and retrognathia (Gibson et al, ; Tatton‐Brown, et al, 2013; Tatton‐Brown et al, ; Weaver, Graham, Thomas, & Smith, ). It has been suggested that Weaver syndrome is also caused by EED constitutive variants (Cooney, Bi, Schlesinger, Vinson, & Potocki, ; Imagawa et al, ; Smigiel et al, ).…”

Section: Introductionmentioning

confidence: 99%

EED and EZH2 constitutive variants: A study to expand the Cohen‐Gibson syndrome phenotype and contrast it with Weaver syndrome

Griffiths

Loveday

Zachariou

et al. 2019

American J of Med Genetics Pt A

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Overgrowth-intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability.Constitutive EED variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen-Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine Cohen-Gibson, EED, EZH2, intellectual disability, overgrowth, WeaverAlthough the current study has permitted further refinement of the EED phenotype, the small numbers of individuals with EED variants preclude robust statistical comparisons. As genomic testing becomes more accessible and more individuals with EED variants are identified, it is likely that we will be able better to define the EED-associated phenotype, draw more robust comparisons with EZH2 phenotype and be able to develop EED specific evidence-based management guidance. ACKNOWLEDGMENTSWe thank the patients and families for their active participation in this study and the clinicians that recruited them. The full list of collaborators is in Supporting Information File S1 but we would particularly like to thank the clinicians who recruited the 47 patients in the study with Weaver syndrome:

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Section: Introductionmentioning

confidence: 99%

EED and EZH2 constitutive variants: A study to expand the Cohen‐Gibson syndrome phenotype and contrast it with Weaver syndrome

Griffiths

Loveday

Zachariou

et al. 2019

American J of Med Genetics Pt A

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“…Craniofacial features are present in patients with SUZ12 , EED and EZH2 mutations, but these appear differently; micrognathia/retrognathia is prominent in those with EED and EZH2 mutations but was not observed in our three patients with a SUZ12 mutation. EZH2 and EED mutation‐positive individuals generally exhibit specific facial phenotypes at birth or early childhood (<1 year) . In contrast, in the two SUZ12 ‐mutated individuals (2 and 3), facial features were noted later at the age of 5 years 5 months and 3 years, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…EZH2 and EED mutationpositive individuals generally exhibit specific facial phenotypes at birth or early childhood (<1 year). [2][3][4][5][6][7][8]10,11,13,14 In contrast, in the two Therefore, pathogenic variants in SUZ12 likely cause a Weaver-like syndrome rather than WS, but further case reports are required.…”

Section: Discussionmentioning

confidence: 99%

“…In 2011, Khosravi et al proposed clinical criteria to support the diagnosis of WS . Pathogenic variants in the genes encoding enhancer of zeste homolog 2 ( EZH2 ) and embryonic ectoderm development ( EED ) have been identified in WS or Weaver‐like syndrome . In particular, EZH2 was previously established as the causative gene for WS; thus, a molecular diagnostic approach is crucial for overgrowth patients .…”

Section: Introductionmentioning

confidence: 99%

“…have been identified in WS or Weaver-like syndrome. [2][3][4][5][6][7][8][9][10][11][12][13][14] In particular, EZH2 was previously established as the causative gene for WS; thus, a molecular diagnostic approach is crucial for overgrowth patients. 11 Nevertheless, individuals with an EZH2 mutation do not always exhibit the classical manifestations of WS.…”

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confidence: 99%

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Novel SUZ12 mutations in Weaver‐like syndrome

Imagawa

Albuquerque

Isidor³

et al. 2018

Clinical Genetics

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SUZ12 is a core component of polycomb repressive complex 2 (PRC2) along with EZH2 and EED. Recently, germline mutations in the SUZ12, EZH2 and EED genes have been reported in Weaver syndrome (WS) or Weaver-like syndrome, suggesting a functional link between PRC2 deficits and WS. However, only one case of a SUZ12 mutation presenting with Weaver-like syndrome has been reported. Here, we report a missense and a frameshift mutation in SUZ12 (c.1797A>C; p.Gln599His and c.844_845del; p.Ala282Glnfs*7), both of which are novel, in two individuals. Their clinical features included postnatal overgrowth, increased bifrontal diameter, large ears, round face, horizontal chin crease and skeletal anomalies, but did not fulfill the WS diagnostic criteria. These data provide strong evidence that SUZ12 mutations cause Weaver-like syndrome.

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Manifestation of epilepsy in a patient with EED‐related overgrowth (Cohen–Gibson syndrome)

Hetzelt

Winterholler²,

Kerling³

et al. 2021

American J of Med Genetics Pt A

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Cohen–Gibson syndrome is a rare genetic disorder, characterized by fetal or early childhood overgrowth and mild to severe intellectual disability. It is caused by heterozygous aberrations in EED, which encodes an evolutionary conserved polycomb group (PcG) protein that forms the polycomb repressive complex‐2 (PRC2) together with EZH2, SUZ12, and RBBP7/4. In total, 11 affected individuals with heterozygous pathogenic variants in EED were reported, so far. All variants affect a few key residues within the EED WD40 repeat domain. By trio exome sequencing, we identified the heterozygous missense variant c.581A > G, p.(Asn194Ser) in exon 6 of the EED‐gene in an individual with moderate intellectual disability, overgrowth, and epilepsy. The same pathogenic variant was detected in 2 of the 11 previously reported cases. Epilepsy, however, was only diagnosed in one other individual with Cohen–Gibson syndrome before. Our findings further confirm that the WD40 repeat domain represents a mutational hotspot; they also expand the clinical spectrum of Cohen–Gibson syndrome and highlight the clinical variability even in individuals with the same pathogenic variant. Furthermore, they indicate a possible association between Cohen–Gibson syndrome and epilepsy.

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Novel de novo mutation affecting two adjacent aminoacids in the EED gene in a patient with Weaver syndrome

Cited by 16 publications

References 7 publications

EED and EZH2 constitutive variants: A study to expand the Cohen‐Gibson syndrome phenotype and contrast it with Weaver syndrome

EED and EZH2 constitutive variants: A study to expand the Cohen‐Gibson syndrome phenotype and contrast it with Weaver syndrome

Novel SUZ12 mutations in Weaver‐like syndrome

Manifestation of epilepsy in a patient with EED‐related overgrowth (Cohen–Gibson syndrome)

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