High-resolution Human Genome Scanning Using Whole-genome BAC Arrays

Constitutional chromosome abnormalities are a frequent cause of many human syndromes, such as infertility, congenital anomalies, and mental retardation (Gardner and Sutherland 1996). Cytogenetic analysis ofchromosomal integrity in patients with mental retardation (MR) indicates that 40% of severe (IQ<55) and10–20% of mild (IQ = 55–70) MR is caused by chromosomal anomalies (Flint et al. 1995). However, due to thepoor resolution of conventional cytogenetic analysis,subtle chromosomal rearrangements (<3 Mb) may bemissed in a significant proportion of mild MR cases. Recent studies focusing on the subtelomeric regions of patients with idiopathic MR indeed indicated that theprevalence of subtle subtelomeric rearrangements couldbe as high as 6% in these patients (Flint et al. 1995;Knight et al. 1999), and it is now widely accepted thatsubmicroscopic telomeric rearrangements are a significant cause of MR. It is quite natural to hypothesize thata substantial proportion of idiopathic MR may be causedby subtle rearrangements in other parts of the genomethat were never detected due to a low resolution of cytogenetic analysis and the unavailability of high-resolution genome-scanning techniques. The fact that chromosomal rearrangements can occur in almost any region ofthe genome (Brewer et al. 1998, 1999), and the existenceof subtle microdeletions and microduplications alongthe chromosomal arms in over 10 clinical syndromes associated with MR (Shapira 1998), support this hypothesis...