Disease and CNVs
Structural abnormalities involving human chromosomes, identified using conventional cytogenetic analysis, are estimated to occur in ~0.5% of newborns. Constitutional chromosomal imbalance is frequently associated with learning disability, dysmorphism, congenital anomalies, and abnormalities of growth. Antenatally ascertained balanced de novo structural rearrangements are associated in ~6% of cases with abnormal phenotype. Current microscopic analysis of the karyotypes of such patients either provide only limited resolution of the rearrangement or fail to detect a rearrangement at all. We are using high resolution analysis (array-CGH and sequencing) to provide rapid diagnosis of chromosome rearrangement/imbalance and to understand the underlying cause of the developmental abnormality in the patient. Specifically, we are using a whole genome tile path array and high resolution redundant targeted arrays for the analysis of sub-microscopic chromosome imbalance in patients with learning disability and dysmorphology and patients with apparently balanced translocation. Of great importance for the identification of potentially significant copy number changes in patients is an understanding of copy number variation in the normal population. We (a Consortium Charles Lee: Brigham Women's Hospital/Harvard; Keith Jones: Affymetrix; Hiroyuki Aburatani: University of Tokyo and Steve Scherer: Hospital for Sick Children/Toronto)have generated a primary CNV map of the human genome by screening all 270 individuals used in the HapMap study with two complementary technologies: the Affymetrix 500k SNP genotyping platform and array-CGH on our whole genome tile path array. To facilitate international collaboration in the analysis of patients with array-CGH, we have developed a WWW-based database, DECIPHER (http://decipher.sanger.ac.uk) which captures both patient phenotype and molecular data and allows visualisation of the rearrangments within the genome browser Ensembl together with normal copy number variation. To further understand the molecular mechanisms involved in constitutional rearrangements leading to disease, our breakpoint analysis is being advanced to the level of the sequence.