Chromosome Microarray and Undiagnosed Seizures in a Pediatric Patient

Abstract

Chromosome microarrays have revolutionized conventional cytogenetics due to their greatly increased resolution, resulting in a greater number of chromosome abnormalities detected. Chromosome microarray analysis is the recommended first tier diagnostic test for children with mental handicap, congenital anomalies/dysmorphisms and autism 1 and results in a much higher diagnostic yield (15%-20%) than a conventional G-band karyotype (approximately 3%, excluding Down syndrome and other recognizable chromosomal syndromes) 1. Numerous conventional chromosome disorders, such as the Wolf-Hirschhorn (4p-), Angelman (15q-), Miller-Dieker (17p-), Klinefelter (XXY), and Down (+21) syndromes, have been reported in association with various neurological disorders, including seizures and epilepsy 2. However, many children with a neurological disorder, such as severe epilepsies, have a normal G-band karyotype with no diagnosis, although a genetic etiology is often suspected 3. Chromosome microarray has recently been reported to detect clinically significant chromosome abnormalities in approximately 9% of patients with a broad range of neurologic phenotypes of unknown etiology, including severe epilepsy 3. For example, a variety of seizures types were reported in association with the newly identified 15q13.3 microdeletion syndrome, detectable only by microarray 2. A conventional G-band karyotype will not reliably detect deletions or duplications smaller than approximately 5 Mb (megabases). Chromosome microarray allows for the detection of unbalanced DNA copy number variations or changes, i.e. deletions and duplications, at resolutions much less than 1 Mb, with the lower limits of resolution in the hundreds of Kb (kilobases) at gene rich regions. DNA segments from across all chromosomes are used as substitutes for metaphase chromosomes, analogous to a molecular karyotype 1. In addition, approximately 40% of patients with a clinical phenotype and an apparently balanced translocation by conventional cytogenetics have been shown, by chromosome microarray, to carry a cryptic imbalance that would be consistent with their clinical phenotype 4. In prenatal diagnosis, therefore, chromosome microarray diagnosis is recommended for fetuses with a de novo chromosome rearrangement 5. We report an apparently balanced, de novo translocation detected prenatally by conventional karyotype in a patient with epilepsy and neurodevelopmental dysfunction of unknown etiology. A postnatal chromosome microarray revealed a cryptic microdeletion at one of the translocation breakpoints. The results of a prenatal microarray would have suggested consideration of THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES