Copy Number Variation Analysis and Discovery of New Genetic Disorders


Recent advances in microarray technology for the genomewide analysis of copy number alterations have enabled Children's Hospital investigators to identify new genetic disorders. The use of this state-of-the-art technology serves as the springboard for new research into the role of cytogenetic abnormalities, or chromosomal rearrangements, in genetic diseases.

Many genetic diseases arise from chromosomal rearrangements like deletions, duplications and unbalanced translocations. These types of rearrangements can lead to the loss or gain of genomic regions containing one or more genes important for development. The diseases resulting from such copy number alterations — designated as "genomic disorders" — occur in about one in every 1,000 live births.

Genomic disorders may manifest in the form of multiple congenital anomalies (MCA), a significant cause of morbidity and mortality in children. Although some genomic disorders like velocardiofacial and DiGeorge syndrome are well characterized, many genomic disorders are undetected because of the limitations of the current techniques used in clinical diagnostics.

Collaborating with Hospital colleagues, Tamim Shaikh, Ph.D., Division of Human Genetics and Molecular Biology, has spearheaded a project to investigate the use of high-resolution, oligonucleotide microarrays for copy number analysis in children with genetic diseases.

"We aim to identify previously undetectable, disease-causing copy number alterations in patients with multiple congenital anomalies," says Dr. Shaikh. "Identifying the genomic regions that are altered in these patients will give us better insight into the mechanisms underlying this group of disorders."

Dr. Shaikh recently received a $2.28 million, 4-year grant from the National Institutes of Health to study copy number alterations in genomic disorders. The goals of this grant include enrolling patients with MCA in collaboration with Dr. Elaine Zackai and her colleagues in the Hospital's Clinical Genetics Center and later conducting copy number analysis using oligonucleotide microarrays.

As part of this grant, Dr. Shaikh is also collaborating with Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics (CAG), to generate a large database of copy number variations in 10,000 controls. Peter White, Ph.D., who heads the Center for Biomedical Informatics (CBMi), and Xiaowu Gai, Ph.D., and colleagues from the Bioinformatics Core (BIC) provide the computational expertise to develop better tools for the copy number analysis.

Dr. Shaikh and his colleagues now routinely use the state-of-the-art oligonucleotide microarray technology to detect copy number alterations in patients who have congenital anomalies of unknown origin. They have been the first to identify patients who have similar clinical traits, or phenotype, and then detecting the same copy number alteration in each of them.

In a paper published in September's Nature Genetics, the investigators reported their discovery of a previously unrecognized syndrome located at chromosome 16p11.2-p12.2. Children with this microdeletion disorder share a phenotype and they are all have a deletion on the same section of DNA in chromosome 16.

Similarly, as reported in the September issue of the journal Genetics in Medicine, Dr. Shaikh and his colleagues found a new microdeletion syndrome of chromosome 1q41-q42. The investigators used a "genotype-first" rather than a "phenotype-first" approach to identifying the chromosomal abnormalities in the patients. Dr. Shaikh will present the findings on the new 1q41q42 syndrome at the annual American Society of Human Genetics meeting in San Diego in October.

"These breakthroughs are possible in large part because Children's Hospital investigators are on the cutting-edge of technology," says Dr. Shaikh. "And the Hospital environment that supports collaboration between divisions, departments and with clinical care encompasses a bench to bedside — and then back to the bench — approach to understanding the causes of these genetic abnormalities and developing better diagnostic tests and treatments."

Dr. Shaikh was recently invited to submit an expert opinion on the use of oligonucleotide microarrays in genome-wide analyses of copy number alterations in patients with mental retardation and/or MCA. Published in the September issue of Genetics in Medicine as part of a special issue sponsored by the American College of Medical Genetics, the article highlights the use of oligonucleotide microarrayswhich allow for a much higher resolution than diagnostic techniques routinely in use in the clinical setting.

Dr. Shaikh anticipates that continued research and collaboration with CAG, CBMi, the Bioinformatics Core and the Clinical Genetics Center will lead to clinical and genomic databases that will then serve as a public resource to guide more accurate patient diagnosis and care.