Gliomas that aggregate in otherwise unremarkable families may have a heritable genetic basis. To determine the spectrum of genetic alterations in glioma-susceptible families, we examined tumor DNA from familial cases for regions of chromosomal gain or loss using comparative genomic hybridization (CGH). We compared chromosomal alterations within and among glioma families to those found in sporadic gliomas. A specific chromosomal abnormality common to the tumors of multiple unrelated probands with glioma or a specific chromosomal abnormality common to multiple affected persons in a single glioma-prone family would support the hypothesis of an inherited predisposition to glioma and at the same time identify specific regions of the genome harboring putative glioma susceptibility genes. Tumor DNA from 11 patients from seven families with two or more individuals with glioma was analyzed, including three members of a remarkable family having 10 affected individuals. We found no chromosomal abnormality common to all tumors of all probands nor did we find family-specific abnormalities in two of three glioma-prone kindreds. There were frequent copy number aberrations (CNAs) on chromosomes 7, 10, 19, and the sex chromosomes; other CNAs included +3q(13.3-29), -4q, +5q, -9q34, +12, -13q(21-->33), -15, -16p, +17qter, -18, -21, and -22. Amplifications occurred at +2 7p(11.1-->12), +2 7q(21.2-->33), +2 12q(13.2-->14), and +2 12p(11-->12). Although there were several novel CNAs [-16p, and +2 12p(11-p12)], none could readily explain the inheritance of these tumors.