Tamim H. Shaikh, Ph.D.
Assistant Professor, Dept of Pediatrics

Genetics and Gene Regulation Program

Address

1010B Abramson Research Center (office)
1003D, Abramson Research Center (lab)
The Children’s Hospital of Philadelphia
3615 Civic Center Blvd.
Philadelphia, PA 19104-4318

Office tel.: 215 590-4274
Lab tel.: 215 590-5256
Fax: 215 590-3764
E-mail: tshaikh@mail.med.upenn.edu

Education

St. Xavier's College, Bombay University, INDIA, B.Sc (Life Sciences and Biochemistry) 1989

Louisiana State University Medical Center, Ph.D. (Molecular Genetics and Genomics) 1995

Research Interests

• Birth Defects, Congenital Anomalies, Genome Architecture, Chromosomal Rearrangements, Genetic Diseases and Genomewide Technologies.

Key words: Genome, Chromosome, Rearrangement, Genetic Diseases, Duplication, Deletion, Translocation, Microarray, Computational Analysis

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Description of Research

The research in my laboratory focuses on genetic diseases that occur due to chromosomal rearrangements such as microdeletions, interstitial duplications, translocations and inversions. Diseases arising from such structural rearrangements have been designated “genomic disorders” and are estimated to occur at a frequency of 0.7-1/1000 live births. These disorders can manifest in the form of multiple congenital anomalies (MCA), which are a significant cause of morbidity and mortality in children. Microdeletions and microduplications can give rise to altered copy number of several genes or may disrupt the integrity of a single gene, causing disease. A few of the better characterized genomic disorders include Prader-Willi (PWS; MIM # 176270) and Angelman syndromes (AS; MIM# 105830)) on 15q11-q13 Williams-Beuren syndrome (WBS; MIM # 194050) on 7q11.23, Smith-Magenis syndrome (SMS; MIM # 182290)/duplication 17p11.2 on 17p11.2 (Chen et al., 1997) and several rearrangements associated with 22q11 including DiGeorge and velocardiofacial syndromes (DGS/VCFS; MIM # 188400) and cat eye syndrome (CES; MIM # 115470). Recently, there has been an increasing awareness that the genomic restructuring that leads to the above disorders is caused by aberrant recombination occurring at segmental duplications. Segmental duplications (SDs) are a class of repetitive DNA elements in the human genome which have resulted from duplication of large segments of genomic DNA ranging in size from 10-500 kb. The duplicated segments share >90% (typically 96-98%) nucleotide sequence identity with each other. This high level of paralogy over large stretches of DNA can lead to aberrant recombination due to misalignment between non-allelic sequences on homologous chromosomes. These regions of genomic instability are expected to be major contributors to the burden of cytogenetic and sub-microscopic chromosomal abnormalities seen in a clinical setting.

It is very likely that many genomic disorders go undetected due to the limitations of current techniques used in clinical diagnostics. Towards this end, we have an ongoing study in collaboration with the Clinical Genetics Center at the Children's Hospital of Philadelphia to investigate the role of copy number alterations of genomic regions in children with multiple birth defects.We use genomewide analysis with high resolution, oligonucleotide microarrays to detect copy number variation in our patients with congenital anomalies of unknown etiology. Our approach has allowed us to detect clinically relevant, submicroscopic rearrangements which were missed by clinical tests. Most of the rearrangements identified are novel and involve several genes. Based on the multiorgan effects of the rearrangements including, developmental delay, craniofacial differences, cardiac defects and mild to severe mental retardation, many or all of these genes that are altered may have significant roles in early human development. We are also investigating the role of copy number or structural variation in common, complex diseases like Bipolar disorder and Schizophrenia. Analysis with high density arrays has also created a need for data analysis and management in my laboratory. Thus, development and refinement of computational tools for analysis and mining of high density datasets is another area of interest. Ongoing projects include discovery of novel rearrangements associated with multiple congenital anomalies; molecular characterization of new genomic disorders, functional analysis of candidate genes and elucidation of mechanisms underlying the rearrangements.

Recent Publications

Ballif, B.C., Hornor, S, Jenkins, E., Madan-Khetarpal, S., Surti, U., Jackson, K., Asamoah, A., Farnsworth, P.L., Gowans, G.C., Conway, R.L., Graham, J.M., Medne, L., Zackai, E.H., Shaikh, T.H., Eis, P.S., Bejjani1, B.A., Shaffer, L.G. Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2 . Nature Genetics 2007 (Epub August 19, 2007)

Shaikh, T.H. Oligonucleotide Arrays for High-resolution Analysis of Copy Number Alteration in Mental Retardation/Multiple Congenital Anomalies. Genet. Med. 2007 (in press)

Shaffer, L.G., Theisen, A., Bejjani1, B.A., Ballif, B.C., Aylsworth, A.S., Curtis, M., Lim, C., McDonald, M., Ellison, J.W., Kostiner, D., Saitta, S., Shaikh, T.H. The Discovery of Microdeletion Syndromes in the Post-Genomic Era: Review of the Methodology and Characterization of a New 1q42 Microdeletion Syndrome. Genet Med. 2007 (in press)

Shaikh TH, O'connor RJ, Pierpont ME, McGrath J, Hacker AM, Nimmakayalu M, Geiger E, Emanuel BS and Saitta SC. Low copy repeats mediate distal chromosome 22q11.2 deletions: Sequence analysis predicts breakpoint mechanisms. Genome Res. 17(4):482-491. 2007

Ming J.E., Geiger E., James A.C., Ciprero K.L., Nimmakayalu M., Zhang Y., Huang A., Vaddi M., Rappaport E., Zackai E.H., and Shaikh T.H. Rapid Detection of Submicroscopic Chromosomal Rearrangements in Children with Multiple Congenital Anomalies using High Density, Oligonucleotide Arrays. Hum. Mutat. 27(5),467-473, 2006

Lab

Rotation Projects

Please contact Dr. Shaikh for details about available projects.

Lab personnel:

Chad Haldeman-Englert, MD- Clinical Fellow
Elizabeth Geiger- Sr. Research Technician.