Constitutional tandem duplication of 9q34 that truncates EHMT1 in a child with ganglioglioma

Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
Pediatric Blood & Cancer (Impact Factor: 2.39). 05/2012; 58(5):801-5. DOI: 10.1002/pbc.23219
Source: PubMed


Point mutations of EHMT1 or deletions and duplications of chromosome 9q34.3 are found in patients with variable neurologic and developmental disorders. Here, we present a child with congenital cataract, developmental and speech delay who developed a metastatic ganglioglioma with progression to anaplastic astrocytoma. Molecular analysis identified a novel constitutional tandem duplication in 9q34.3 with breakpoints in intron 1 of TRAF2 and intron 16 of EHMT1 generating a fusion transcript predicted to encode a truncated form of EHMT1. The ganglioglioma showed complex chromosomal aberrations with further duplication of the dup9q34. Thus, this unique tandem 9q34.3 duplication may impact brain tumor formation.

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    • "ASD autistic spectrum disorder, CNV copy number variant, DD developmental delay, F female, ID intellectual disability, M male, MCA multiple congenital anomalies, ND not determined a Results of molecular analysis on this patient is reported by Cheung et al. (2011) Hum Genet that increased dosage of EHMT1 may be responsible for the neurodevelopmental impairment, speech delay, and autism spectrum disorders in these patients. We were not able to correlate the specific differences in clinical severity between patients with duplications and triplications leading to further increase in dosage of the EHMT1 gene due to variability in size and gene content in each patient, the variability of the duplication phenotype, and the limited number of triplication patients available for study. "
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    ABSTRACT: Constitutional deletions of distal 9q34 encompassing the EHMT1 (euchromatic histone methyltransferase 1) gene, or loss-of-function point mutations in EHMT1, are associated with the 9q34.3 microdeletion syndrome, also known as Kleefstra syndrome [MIM#610253]. We now report further evidence for genomic instability of the subtelomeric 9q34.3 region as evidenced by copy number gains of this genomic interval that include duplications, triplications, derivative chromosomes and complex rearrangements. Comparisons between the observed shared clinical features and molecular analyses in 20 subjects suggest that increased dosage of EHMT1 may be responsible for the neurodevelopmental impairment, speech delay, and autism spectrum disorders revealing the dosage sensitivity of yet another chromatin remodeling protein in human disease. Five patients had 9q34 genomic abnormalities resulting in complex deletion-duplication or duplication-triplication rearrangements; such complex triplications were also observed in six other subtelomeric intervals. Based on the specific structure of these complex genomic rearrangements (CGR) a DNA replication mechanism is proposed confirming recent findings in Caenorhabditis elegans telomere healing. The end-replication challenges of subtelomeric genomic intervals may make them particularly prone to rearrangements generated by errors in DNA replication.
    Full-text · Article · Aug 2012 · Human Genetics
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    ABSTRACT: Precise transcriptional networks drive the orchestration and execution of complex developmental processes. Transcription factors possessing sequence-specific DNA binding properties activate or repress target genes in a step-wise manner to control most cell lineage decisions. This regulation often requires the interaction between transcription factors and subunits of massive protein complexes that bear enzymatic activities towards histones. The functional coupling of transcription proteins and histone modifiers underscores the importance of transcriptional regulation through chromatin modification in developmental cell fate decisions and in disease pathogenesis.
    Full-text · Article · Apr 2012 · Epigenomics

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