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Large genomic rearrangements in the CFTR gene contribute to CBAVD.

ABSTRACT: BACKGROUND: By performing extensive scanning of whole coding and flanking sequences of the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, we had previously identified point mutations in 167 out of 182 (91.7%) males with isolated congenital bilateral absence of the vas deferens (CBAVD). Conventional PCR-based methods of mutation analysis do not detect gross DNA lesions. In this study, we looked for large rearrangements within the whole CFTR locus in the 32 CBAVD patients with only one or no mutation. METHODS: We developed a semi-quantitative fluorescent PCR assay (SQF-PCR), which relies on the comparison of the fluorescent profiles of multiplex PCR fragments obtained from different DNA samples. We confirmed the gross alterations by junction fragment amplification and identified their breakpoints by direct sequencing. RESULTS: We detected two large genomic heterozygous deletions, one encompassing exon 2 (c.54-5811_c.164+2186del8108ins182) [or CFTRdele2], the other removing exons 22 to 24 (c.3964-3890_c.4443+3143del9454ins5) [or CFTRdele 22_24], in two males carrying a typical CBAVD mutation on the other parental CFTR allele. We present the first bioinformatic tool for exon phasing of the CFTR gene, which can help to rename the exons and the nomenclature of small mutations according to international recommendations and to predict the consequence of large rearrangements on the open reading frame. CONCLUSION: Identification of large rearrangements further expands the CFTR mutational spectrum in CBAVD and should now be systematically investigated. We have designed a simple test to specifically detect the presence or absence of the two rearrangements identified in this study.

SUBMITTER: Taulan M

PROVIDER: S-EPMC1876208 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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Large genomic rearrangements in the CFTR gene contribute to CBAVD.

Taulan Magali M Girardet Anne A Guittard Caroline C Altieri Jean-Pierre JP Templin Carine C Beroud Christophe C des Georges Marie M Claustres Mireille M

BMC medical genetics 20070420

<h4>Background</h4>By performing extensive scanning of whole coding and flanking sequences of the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, we had previously identified point mutations in 167 out of 182 (91.7%) males with isolated congenital bilateral absence of the vas deferens (CBAVD). Conventional PCR-based methods of mutation analysis do not detect gross DNA lesions. In this study, we looked for large rearrangements within the whole CFTR locus in the 32 CBAVD patients ...[more]

PMID: 17448246

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Project description:BackgroundRecently we developed a gene orthology inference tool based on genome rearrangements (Journal of Bioinformatics and Computational Biology 19:6, 2021). Given a set of genomes our method first computes all pairwise gene similarities. Then it runs pairwise ILP comparisons to compute optimal gene matchings, which minimize, by taking the similarities into account, the weighted rearrangement distance between the analyzed genomes (a problem that is NP-hard). The gene matchings are then integrated into gene families in the final step. The mentioned ILP includes an optimal capping that connects each end of a linear segment of one genome to an end of a linear segment in the other genome, producing an exponential increase of the search space.ResultsIn this work, we design and implement a heuristic capping algorithm that replaces the optimal capping by clustering (based on their gene content intersections) the linear segments into [Formula: see text] subsets, whose ends are capped independently. Furthermore, in each subset, instead of allowing all possible connections, we let only the ends of content-related segments be connected. Although there is no guarantee that m is much bigger than one, and with the possible side effect of resulting in sub-optimal instead of optimal gene matchings, the heuristic works very well in practice, from both the speed performance and the quality of computed solutions. Our experiments on primate and fruit fly genomes show two positive results. First, for complete assemblies of five primates the version with heuristic capping reports orthologies that are very similar to the orthologies computed by the version of our tool with optimal capping. Second, we were able to efficiently analyze fruit fly genomes with incomplete assemblies distributed in hundreds or even thousands of contigs, obtaining gene families that are very similar to [Formula: see text] families. Indeed, our tool inferred a higher number of complete cliques, with a higher intersection with [Formula: see text], when compared to gene families computed by other inference tools. We added a post-processing for refining, with the aid of the [Formula: see text] algorithm, our ambiguous families (those with more than one gene per genome), improving even more the accuracy of our results. Our approach is implemented into a pipeline incorporating the pre-computation of gene similarities and the post-processing refinement of ambiguous families with [Formula: see text]. Both the original version with optimal capping and the new modified version with heuristic capping can be downloaded, together with their detailed documentations, at https://gitlab.ub.uni-bielefeld.de/gi/FFGC or as a Conda package at https://anaconda.org/bioconda/ffgc .

Dataset Information

Large genomic rearrangements in the CFTR gene contribute to CBAVD.

Publications

Large genomic rearrangements in the CFTR gene contribute to CBAVD.

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