19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression

被引:12
作者
Lehman, A. M. [1 ,2 ,3 ]
du Souich, C. [1 ,2 ,3 ]
Chai, D. [4 ]
Eydoux, P. [4 ]
Huang, J. L. [1 ,3 ]
Fok, A. K. [1 ,3 ,5 ]
Avila, L. [1 ,3 ,5 ]
Swingland, J. [6 ]
Delaney, A. D. [7 ]
McGillivray, B. [1 ,3 ]
Goldowitz, D. [1 ,3 ,5 ]
Argiropoulosh, B. [8 ]
Kobor, M. S. [1 ,3 ,5 ]
Boerkoel, C. F. [1 ,2 ,3 ]
机构
[1] Univ British Columbia, Dept Med Genet, Childrens & Womens Hlth Ctr British Columbia, Vancouver, BC V6H 3N1, Canada
[2] Univ British Columbia, Rare Dis Fdn, Vancouver, BC V6H 3N1, Canada
[3] Univ British Columbia, Child & Family Res Inst, Vancouver, BC V6H 3N1, Canada
[4] Univ British Columbia, Dept Pathol, Vancouver, BC V6H 3N1, Canada
[5] Univ British Columbia, Ctr Mol Med & Therapeut, Vancouver, BC V6H 3N1, Canada
[6] Univ London Imperial Coll Sci Technol & Med, MRC Clin Sci Ctr, London, England
[7] Univ British Columbia, Genome Sci Ctr, Vancouver, BC V6H 3N1, Canada
[8] Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON K1H 8L1, Canada
关键词
copy number variant; genomic disorder; intellectual disability; macrocephaly; microduplication; overgrowth; methylation; Sotos syndrome; COPY NUMBER VARIATION; DOWN-SYNDROME; MECP2; NSD1; REARRANGEMENTS; DUPLICATIONS; ARCHITECTURE; DISEASE; IMPACT; BRAIN;
D O I
10.1111/j.1399-0004.2010.01615.x
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Up to 90% of individuals affected by Sotos syndrome have a pathogenic alteration of NSD1 (encodes nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1), a histone methyltransferase that functions as both a transcriptional activator and a repressor. Genomic copy number variations may also cause a Sotos-like phenotype. We evaluated a three-generation family segregating a Sotos-like disorder characterized by typical facial features, overgrowth, learning disabilities, and advanced bone age. Affected individuals did not have a detectable NSD1 mutation, but rather were found to have a 1.9 Mb microduplication of 19p13.2 with breakpoints in two highly homologous Alu elements. Because the duplication included the DNA methyltransferase gene (DNMT1), we assessed DNA methylation of peripheral blood and buccal cell DNA and detected no alterations. We also examined peripheral blood gene expression and found evidence for increased expression of genes within the duplicated region. We conclude that microduplication of 19p13.2 is a novel genomic disorder characterized by variable neurocognitive disability, overgrowth, and facial dysmorphism similar to Sotos syndrome. Failed compensation of gene duplication at the transcriptional level, as seen in peripheral blood, supports gene dosage as the cause of this disorder.
引用
收藏
页码:56 / 63
页数:8
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