The FRA14B common fragile site maps to a region prone to somatic and germline rearrangements within the large GPHN gene

Abstract

Common fragile sites (cFSs) represent parts of the normal chromosome structure susceptible to breakage under replication stress. Although only a small number of cFSs have been molecularly characterized, genomic damage of cFS genes appears to be critical for the development of various human diseases. In this study, we fine mapped the location of FRA14B and showed that the fragile region spans 765 kb at 14q23.3, containing the large gephyrin (GPHN) gene. The FRA14B sequence is enriched in perfect A/T>24 stretches and R‐loop forming sequences (RLFS), and harbors a large palindromic motif in the core region. FRA14B instability is not only limited to lymphocytes, but also occurs in neuroblastoma and breast epithelial cells. Using array comparative genomic hybridization (CGH), we examined copy number alteration patterns within FRA14B in a panel of 180 cancer cell lines and primary tumors. Our CGH data and a survey of 1046 Cancer Cell Line Encyclopedia profiles demonstrate that focal deletions cluster within FRA14B and disrupt the genomic integrity of GPHN in approximately 5% of cancer cells. Moreover, germline CNVs (copy number variants) profiles provided by the Database of Genomic Variants and available literature suggest that germline CNVs and rare pathogenic deletions associated with neurodevelopmental disorders cluster within the core fragile region of GPHN. Overall, our data provide insight into the molecular structure of FRA14B, and identify GPHN, as a large cFS gene in the human genome, whose disruption appears to trigger various neurodevelopmental diseases.

Fragile sites, chromosomal lesions, tandem repeats, and disease

“…Increasingly finer mapping is conducted with contiguous multi-colored BAC probes spanning smaller and smaller lengths across the break point until an exact breakage boundary can be determined. The specific sequence of this region along with the encompassing genes are then identified through programs such as RepeatMasker and through human genome sequence databases ( Hormozian et al, 2007 ; Zheglo et al, 2019 ). The identification of these specific fragile site-associated genes can initiate further studies on the role of fragile sites in human genetic diseases and cancer.…”

Common Threads: Aphidicolin-Inducible and Folate-Sensitive Fragile Sites in the Human Genome

“…Fragile sites are all thought to be regions of the genome that for some reason are slow to complete replication, and their presence is associated with a variety of chromosome abnormalities. Genome instability at CFSs is thought to be a driving force for tumorigenesis with APH-CFSs being associated with copy number variations, including a variety of recurrent cancer deletions ( Le Tallec et al, 2013 ; Wilson et al, 2015 ; Zheglo et al, 2019 ). Some CFS-associated CNVs are also associated with neurological disorders ( Denison et al, 2003 ; Ambroziak et al, 2015 ; Zheglo et al, 2019 ).…”

“…Genome instability at CFSs is thought to be a driving force for tumorigenesis with APH-CFSs being associated with copy number variations, including a variety of recurrent cancer deletions ( Le Tallec et al, 2013 ; Wilson et al, 2015 ; Zheglo et al, 2019 ). Some CFS-associated CNVs are also associated with neurological disorders ( Denison et al, 2003 ; Ambroziak et al, 2015 ; Zheglo et al, 2019 ). CFSs are also frequent sites of viral integration associated with cancer ( Thorland et al, 2000 ; Yu et al, 2005 ).…”