Human genome disorders and genomic architecture
General background
Genomic disorders encompass a group of clinical conditions caused by DNA rearrangements involving unstable regions in the human genome. Many genomic disorders have so far remained undetected because the rearrangements involved are below the detection limit of conventional cytogenetic technologies. Genomic tools like microarray-based comparative genomic hybridization and high-throughput sequencing now allow mapping of genomic copy number alterations at the submicroscopic level, directly linking disease phenotypes to gene dosage alterations. These approaches are excellently suited for the identification of novel genomic disorders, for genotype-phenotype correlation studies, as well as for molecular karyotyping in a routine clinical setting.
Objective
Identifying and characterize novel genomic disorders, thereby improving our understanding of genomic architectural mechanisms underlying the vast burden of cytogenetic abnormalities seen in a clinical setting.
Approach
This proposal is subdivided into 4 parts:
1. Novel genomic disorders will be identified by screening multiple cohorts of clinically well-defined malformation syndromes as well as non-syndromic cases with mental retardation and/or congenital anomalies onto the highest resolution genomic microarrays. The identification of recurrent genomic alterations causing a similar phenotype points to a novel genomic disorder
2. For these disorders, we will elucidate the underlying genomic architectural mechanisms by a combination of in-depth bioinformatic and molecular analyses, studying the presence and nature of repeat sequences and other recombination-prone motifs
3. For all chromosomal rearrangements detected, we will look at patterns of inheritance, at the presence of predisposing inversion polymorphisms or balanced chromosomal translocations in the parents, and at a possible relation with parental age
4. We will search for specific genes located in recurrent rearrangements and analyse them for the presence of causative intragenic mutations in a cohort of patients with similar phenotypes but without apparent chromosomal rearrangements
Go back
