Mission Statement:

Studies of developmental processes are making significant contributions to the understanding of the pathogenesis of human developmental disorders. Since most developmental pathways are controlled by genetic factors, the identification of causative genes in congenital birth defect and the analysis of their developmental effects will greatly facilitate the understanding of underlying genetic control mechanism.

In a number of genetic diseases, structural chromosomal changes that segregate with the disease phenotype have served to map the causative genes to specific chromosomal regions. In this regard, Mendelian cytogenetics refers to the association between chromosomal rearrangements and single gene disorders. De novo chromosome translocations have been widely used for the mapping and cloning of disease genes. In these cases, translocation breakpoints provide important information about the gene location. Balanced chromosome translocations or inversions are rare chromosomal mutations of monogenic developmental disorders which are used to close the disease-causing gene in many genetic diseases.

Most of these balanced reciprocal chromosomal anomalies are sporadic such that the breakpoint disrupts the disease gene directly or dysregulates it indirectly by positional effect. Therefore, finding the exact position of a gene disrupted at the breakpoint can lead to the identification of a disease gene by the screening of patients with similar phenotype but without chromosomal anomalies.

In addition, it has become increasingly clear that microdeletion syndromes are largely due to the phenotypic effects of haploinsuffiency for single genes. This is seen in Smith-Magenis syndrome, Angelman syndrome and DiGeorge syndrome II. Consequently, microdeletions or microduplications have also become instrumental for the identification of disease genes

The Long-term goals of this project are:

understanding the developmental pathway, whose mis-regulation generates human genetic diseases

treatment of human developmental diseases which have a genetic basis.

This being said, the practical aim of this project can be stipulated as the following:

identification of chromosomal anomalies in patients with developmental diease via the karyotyping of patient cell lines (mainly either fibroblast cells or lymphoblastoid cell lines) and high-resolution CGH array technology using patient DNA.

to solicit patients that fit the above criteria from researchers, via case reporting or karyotype screening

soliciting patient DNA with a phenotype reminiscent of the ones seen in balanced chromosomal anomaly patients enrolled on the list of positional cloning. This can be done via literature search and correspondence with clinicians and researchers or via consent by the MCG patients in this study.

cloning and characterization of breakpoint genes in human chromosomal anomalies, prior to verification as the causative gene of phenotype seen in patient with chromosomal defects.

mutation screening of patients samples after functional or positional candidate gene identification and functional analysis of protein coded by causative genes to elucidate underlying developmental mechanisms.