title: 19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Lehman
authors.forename: C
authors.initials: C
authors.lastname: du Souich
authors.forename: D
authors.initials: D
authors.lastname: Chai
authors.forename: P
authors.initials: P
authors.lastname: Eydoux
authors.forename: J L
authors.initials: JL
authors.lastname: Huang
authors.forename: A K
authors.initials: AK
authors.lastname: Fok
authors.forename: L
authors.initials: L
authors.lastname: Avila
authors.forename: J
authors.initials: J
authors.lastname: Swingland
authors.forename: A D
authors.initials: AD
authors.lastname: Delaney
authors.forename: B
authors.initials: B
authors.lastname: McGillivray
authors.forename: D
authors.initials: D
authors.lastname: Goldowitz
authors.forename: B
authors.initials: B
authors.lastname: Argiropoulos
authors.forename: M S
authors.initials: MS
authors.lastname: Kobor
authors.forename: C F
authors.initials: CF
authors.lastname: Boerkoel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D020087:Alu Elements; D002648:Child; D002675:Child, Preschool; D058674:Chromosome Duplication; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D007223:Infant; D007859:Learning Disabilities / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010641:Phenotype; D058495:Sotos Syndrome / Q000235:genetics*
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human