Human Genetics

, Volume 131, Issue 12, pp 1895–1910 | Cite as

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

  • Svetlana A. YatsenkoEmail author
  • Patricia Hixson
  • Erin K. Roney
  • Daryl A. Scott
  • Christian P. Schaaf
  • Yu-tze Ng
  • Robbin Palmer
  • Richard B. Fisher
  • Ankita Patel
  • Sau Wai Cheung
  • James R. LupskiEmail author
Original Investigation


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.


Autism Spectrum Disorder Bacterial Artificial Chromosome Fish Analysis Copy Number Gain Subtelomeric Region 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We are thankful to the families for their cooperation. This study was supported in part by grants the IDDRC (Intellectual and Developmental Disabilities Research Center (P30 HD024064) and the National Institute of Neurological Disorders and Stroke (R01 NS058529) to JRL.

Conflict of interest

J.R.L is a consultant for Athena Diagnostics, owns stock in 23andMe and Ion Torrent Systems Inc., and is a co-inventor on multiple US and European patents for DNA diagnostics. Furthermore, the Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular diagnostic testing (MGL,

Supplementary material

439_2012_1216_MOESM1_ESM.doc (44 kb)
Supplementary material 1 (DOC 43 kb)


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Svetlana A. Yatsenko
    • 1
    • 2
    • 3
    Email author
  • Patricia Hixson
    • 1
  • Erin K. Roney
    • 1
  • Daryl A. Scott
    • 1
  • Christian P. Schaaf
    • 1
  • Yu-tze Ng
    • 4
  • Robbin Palmer
    • 5
  • Richard B. Fisher
    • 6
  • Ankita Patel
    • 1
  • Sau Wai Cheung
    • 1
  • James R. Lupski
    • 1
    • 7
    • 8
    Email author
  1. 1.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  2. 2.Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of PittsburghPittsburghUSA
  3. 3.Department of Pathology, School of MedicineUniversity of PittsburghPittsburghUSA
  4. 4.Barrow Neurological InstitutePhoenixUSA
  5. 5.Northern Nevada Genetic CounselingRenoUSA
  6. 6.Teesside Genetics UnitThe James Cook University HospitalMiddlesbroughUK
  7. 7.Department of PediatricsBaylor College of MedicineHoustonUSA
  8. 8.Texas Children’s HospitalHoustonUSA

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