Constitutional Chromoanagenesis of Distal 13q in a Young Adult with Recurrent Strokes

Abstract

Constitutional chromoanagenesis events, which include chromoanasynthesis and chromothripsis and result in highly complex rearrangements, have been reported for only a few individuals. While rare, these phenomena have likely been underestimated in a constitutional setting as technologies that can accurately detect such complexity are relatively new to the mature field of clinical cytogenetics. G-banding is not likely to accurately identify chromoanasynthesis or chromothripsis, since the banding patterns of chromosomes are likely to be misidentified or oversimplified due to a much lower resolution. We describe a patient who was initially referred for cytogenetic testing as a child for speech delay. As a young adult, he was referred again for recurrent strokes. Chromosome analysis was performed, and the rearrangement resembled a simple duplication of 13q32q34. However, SNP microarray analysis showed a complex pattern of copy number gains and a loss consistent with chromoanasynthesis involving distal 13q (13q32.1q34). This report emphasizes the value of performing microarray analysis for individuals with abnormal or complex chromosome rearrangements.

Genomic Chaos (Multiple Copy Number Variations and Structural Reorganization) Detected in Two Prenatal Cases

“…At least 16 breakpoints and 8 de novo copy number gains detected in a prenatal study should be enough for suspecting fetal consequences, even without sonographic markers. In fact, chromoanasynthesis has been reported in some cases to induce significant gene dosage imbalances and gene disruptions that can have clinical consequences [Liu et al, 2011;Plaisancié et al, 2014;Burnside et al, 2016]. However, a selection bias toward dosage imbalances with no or little phenotypic effects exists, since fetuses with such structural variations are more viable.…”

How Chaotic Is Genome Chaos?

“…Chromoanasynthesis has been found to account for CNV of oncogenic loci in breast cancer [92], B-cell lymphoma [93], mouse brain tumors [94], and on three separate chromosomes, 6, 7 and 12 in a renal leiomyosarcoma [95]. There are also examples of congenital germline chromoanasynthesis on human chromosomes 1 [96] and 21 [97] without obvious pathology but deleterious effects on chromosome 9 [98], 11 [99], 13 [100], 14 [101], and 18 [102].…”

Copy Number Variation and Risk of Stroke

“…Parallel SNP-microarray analysis revealed a complex rearrangement with multiple duplications. 29 Some studies associated stroke with numerical aberrations including trisomy 21, 30 Klinefelter syndrome 31 and Turner syndrome. 32 Somatic loss of the Y-chromosome is a common acquired aberration in male blood cells associated with age and smoking.…”