19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression
| Autor: | Kobor, J Swingland, Dan Goldowitz, B Argiropoulos, AK Fok, Anna Lehman, L Avila, Patrice Eydoux, Cornelius F. Boerkoel, David Chai, Allen Delaney, Barbara McGillivray, C. du Souich, JL Huang |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
DNA (Cytosine-5-)-Methyltransferase 1 Male Adolescent DNA Mutational Analysis Biology medicine.disease_cause Gene dosage Craniofacial Abnormalities Alu Elements Chromosome Duplication Gene duplication Genetics medicine Humans DNA (Cytosine-5-)-Methyltransferases Copy-number variation Child Genetics (clinical) Aged Oligonucleotide Array Sequence Analysis Regulation of gene expression Mutation Sotos Syndrome Genome Human Learning Disabilities Sotos syndrome Infant DNA Methylation Middle Aged medicine.disease Molecular biology Pedigree Phenotype Gene Expression Regulation Child Preschool DNA methylation Leukocytes Mononuclear DNMT1 Female Chromosomes Human Pair 19 |
| Zdroj: | Clinical Genetics. 81:56-63 |
| ISSN: | 0009-9163 |
| DOI: | 10.1111/j.1399-0004.2010.01615.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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