Rare SUZ12 variants commonly cause an overgrowth phenotype

被引:25
作者
Cyrus, Sharri S. [1 ,2 ]
Cohen, Ana S. A. [1 ,2 ]
Agbahovbe, Ruky [1 ,2 ]
Avela, Kristiina [3 ]
Yeung, Kit S. [4 ]
Chung, Brian H. Y. [4 ]
Luk, Ho-Ming [5 ]
Tkachenko, Nataliya [6 ]
Choufani, Sanaa [7 ]
Weksberg, Rosanna [7 ,8 ,9 ,10 ]
Lopez-Rangel, Elena [11 ]
Brown, Kathleen [12 ]
Saenz, Margarita S. [12 ]
Svihovec, Shayna [12 ]
McCandless, Shawn E. [12 ]
Bird, Lynne M. [13 ,14 ]
Garcia, Aixa G. [15 ]
Gambello, Michael J. [15 ]
McWalter, Kirsty [16 ]
Schnur, Rhonda E. [16 ]
An, Jianghong [17 ,18 ]
Jones, Steven J. M. [1 ,17 ,18 ,19 ]
Bhalla, Sanjiv K. [20 ,21 ]
Pinz, Hailey [22 ]
Braddock, Stephen R. [22 ]
Gibson, William T. [1 ,2 ]
机构
[1] Univ British Columbia, Dept Med Genet, 950 West 28th Ave, Vancouver, BC V5Z 4H4, Canada
[2] British Columbia Childrens Hosp, Res Inst, Vancouver, BC, Canada
[3] HUSLAB, Helsinki Univ Hosp, Dept Clin Genet, Helsinki, Finland
[4] Univ Hong Kong, Dept Paediat & Adolescent Med, Hong Kong, Peoples R China
[5] Dept Hlth, Clin Genet Serv, Hong Kong, Peoples R China
[6] Porto Hosp Ctr, Med Genet Ctr Dr Jacinto de Magalhaes, Med Genet Serv, Porto, Portugal
[7] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON, Canada
[8] Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON, Canada
[9] Univ Toronto, Dept Pediat, Toronto, ON, Canada
[10] Univ Toronto, Inst Med Sci, Toronto, ON, Canada
[11] British Columbia Childrens Hosp, Dept Med Genet, Vancouver, BC, Canada
[12] Univ Colorado, Childrens Hosp Colorado, Dept Pediat, Sect Genet & Metab, Anschutz Med Campus, Aurora, CO USA
[13] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA
[14] Rady Childrens Hosp San Diego, Genet Dysmorphol, San Diego, CA USA
[15] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA
[16] GeneDx, Clin Genom, Gaithersburg, MD USA
[17] Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada
[18] British Columbia Canc Agcy, Vancouver, BC, Canada
[19] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC, Canada
[20] Univ British Columbia, Dept Radiol, Vancouver, BC, Canada
[21] Surrey Mem Hosp, Diagnost & Med Imaging Serv, Surrey, BC, Canada
[22] St Louis Univ, Sch Med, Dept Pediat, Div Med Genet, St Louis, MO 63104 USA
基金
加拿大健康研究院;
关键词
Cohen-Gibson syndrome; Polycomb repressive complex 2; SUZ12; SUZ12-related overgrowth; Weaver syndrome; REPRESSIVE COMPLEX 2; NONALLELIC HOMOLOGOUS RECOMBINATION; EED-ASSOCIATED OVERGROWTH; HISTONE METHYLTRANSFERASE; WEAVER SYNDROME; MUTATIONS; GENE; PRC2; INACTIVATION; GENOTYPE;
D O I
10.1002/ajmg.c.31748
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2-related overgrowth) and Cohen-Gibson syndrome (EED-related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver-like phenotype with a rare coding SUZ12 variant-the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver-like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre- and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly-affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically-recognizable syndromes emerge from different variant subtypes.
引用
收藏
页码:532 / 547
页数:16
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