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Understanding the impact of 1q21.1 copy number variant

Chansonette Harvard12, Emma Strong12, Eloi Mercier3, Rita Colnaghi4, Diana Alcantara4, Eva Chow5, Sally Martell12, Christine Tyson6, Monica Hrynchak6, Barbara McGillivray7, Sara Hamilton7, Sandra Marles8, Aziz Mhanni8, Angelika J Dawson8, Paul Pavlidis3, Ying Qiao127, Jeanette J Holden10119, Suzanne ME Lewis1107, Mark O'Driscoll4* and Evica Rajcan-Separovic12*

Author Affiliations

1 Child and Family Research Institute, Molecular Cytogenetics and Array Laboratory, 950 West 28th Avenue, Vancouver, BC, Canada

2 Department of Pathology, University of British Columbia, Vancouver, BC, Canada

3 Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada

4 Human DNA Damage Response Disorders Group, Genome Damage & Stability Centre, University of Sussex, Brighton, UK

5 Clinical Genetics Service, Centre for Addiction and Mental Health, Toronto, and Department of Psychiatry, University of Toronto, Canada

6 Cytogenetics Laboratory, Royal Columbian Hospital, New Westminster, BC, Canada

7 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

8 Departments of Pediatrics and Child Health and Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada

9 Department of Physiology, Queen's University, Kingston, Ontario, Canada

10 Department of Psychiatry, Queen's University, Kingston, Ontario, Canada

11 Genetics and Genomics Research Laboratory, Ongwanada, Kingston, Ontario, Canada

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Orphanet Journal of Rare Diseases 2011, 6:54  doi:10.1186/1750-1172-6-54

Published: 8 August 2011



1q21.1 Copy Number Variant (CNV) is associated with a highly variable phenotype ranging from congenital anomalies, learning deficits/intellectual disability (ID), to a normal phenotype. Hence, the clinical significance of this CNV can be difficult to evaluate. Here we described the consequences of the 1q21.1 CNV on genome-wide gene expression and function of selected candidate genes within 1q21.1 using cell lines from clinically well described subjects.

Methods and Results

Eight subjects from 3 families were included in the study: six with a 1q21.1 deletion and two with a 1q21.1 duplication. High resolution Affymetrix 2.7M array was used to refine the 1q21.1 CNV breakpoints and exclude the presence of secondary CNVs of pathogenic relevance. Whole genome expression profiling, studied in lymphoblast cell lines (LBCs) from 5 subjects, showed enrichment of genes from 1q21.1 in the top 100 genes ranked based on correlation of expression with 1q21.1 copy number. The function of two top genes from 1q21.1, CHD1L/ALC1 and PRKAB2, was studied in detail in LBCs from a deletion and a duplication carrier. CHD1L/ALC1 is an enzyme with a role in chromatin modification and DNA damage response while PRKAB2 is a member of the AMP kinase complex, which senses and maintains systemic and cellular energy balance. The protein levels for CHD1L/ALC1 and PRKAB2 were changed in concordance with their copy number in both LBCs. A defect in chromatin remodeling was documented based on impaired decatenation (chromatid untangling) checkpoint (DCC) in both LBCs. This defect, reproduced by CHD1L/ALC1 siRNA, identifies a new role of CHD1L/ALC1 in DCC. Both LBCs also showed elevated levels of micronuclei following treatment with a Topoisomerase II inhibitor suggesting increased DNA breaks. AMP kinase function, specifically in the deletion containing LBCs, was attenuated.


Our studies are unique as they show for the first time that the 1q21.1 CNV not only causes changes in the expression of its key integral genes, associated with changes at the protein level, but also results in changes in their known function, in the case of AMPK, and newly identified function such as DCC activation in the case of CHD1L/ALC1. Our results support the use of patient lymphoblasts for dissecting the functional sequelae of genes integral to CNVs in carrier cell lines, ultimately enhancing understanding of biological processes which may contribute to the clinical phenotype.