Human subtelomeric copy number gains suggest a DNA replication mechanism for formation: beyond breakage–fusion–bridge for telomere stabilization

• Published in: Human genetics 2012-12, Vol.131 (12), p.1895-1910
• Main Authors: Yatsenko, Svetlana A., Hixson, Patricia, Roney, Erin K., Scott, Daryl A., Schaaf, Christian P., Ng, Yu-tze, Palmer, Robbin, Fisher, Richard B., Patel, Ankita, Cheung, Sau Wai, Lupski, James R.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Analysis; Autism; Base Sequence; Biomedical and Life Sciences; Biomedicine; Caenorhabditis elegans; Child; Child, Preschool; Chromatin remodeling; Chromosome Deletion; Chromosomes; Chromosomes, Human, Pair 9 - genetics; Chromosomes, Human, Pair 9 - metabolism; Comparative Genomic Hybridization; copy number; Craniofacial Abnormalities - genetics; Craniofacial Abnormalities - metabolism; DNA; DNA biosynthesis; DNA Breaks; DNA Copy Number Variations; DNA replication; DNA Replication - genetics; Drug dosages; Female; Gene deletion; Gene Function; Genetic counseling; Genomic Instability; Heart Defects, Congenital - genetics; Heart Defects, Congenital - metabolism; histone methyltransferase; Histone-Lysine N-Methyltransferase - genetics; Human Genetics; Humans; In Situ Hybridization, Fluorescence; Infant; Intellectual Disability - genetics; Intellectual Disability - metabolism; Male; Metabolic Diseases; Models, Genetic; Molecular Medicine; Neurodevelopmental disorders; Original Investigation; Point mutation; Replication; speech; Telomerase; Telomere - genetics; Telomere - metabolism; Telomeres; Yeast
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-012-1216-9

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.