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Clinical and molecular characterization of cystinuria in a French cohort: relevance of assessing large-scale rearrangements and splicing variants.

ABSTRACT: Cystinuria is an autosomal recessive disorder of dibasic amino acid transport in the kidney and the intestine leading to increased urinary cystine excretion and nephrolithiasis. Two genes, SLC3A1 and SLC7A9, coding respectively for rBAT and b0,+AT, account for the genetic basis of cystinuria.This study reports the clinical and molecular characterization of a French cohort including 112 cystinuria patients and 25 relatives from 99 families. Molecular screening was performed using sequencing and Quantitative Multiplex PCR of Short Fluorescent Fragments analyses. Functional minigene-based assays have been used to characterize splicing variants.Eighty-eight pathogenic nucleotide changes were identified in SLC3A1 (63) and SLC7A9 (25) genes, of which 42 were novel. Interestingly, 17% (15/88) and 11% (10/88) of the total number of variants correspond, respectively, to large-scale rearrangements and splicing mutations. Functional minigene-based assays were performed for six variants located outside the most conserved sequences of the splice sites; three variants affect splice sites, while three others modify exonic splicing regulatory elements (ESR), in good agreement with a new in silico prediction based on ?tESRseq values.This report expands the spectrum of SLC3A1 and SLC7A9 variants and supports that digenic inheritance is unlikely. Furthermore, it highlights the relevance of assessing large-scale rearrangements and splicing mutations to fully characterize cystinuria patients at the molecular level.

SUBMITTER: Gaildrat P

PROVIDER: S-EPMC5511796 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Clinical and molecular characterization of cystinuria in a French cohort: relevance of assessing large-scale rearrangements and splicing variants.

Gaildrat Pascaline P Lebbah Said S Tebani Abdellah A Sudrié-Arnaud Bénédicte B Tostivint Isabelle I Bollee Guillaume G Tubeuf Hélène H Charles Thomas T Bertholet-Thomas Aurelia A Goldenberg Alice A Barbey Frederic F Martins Alexandra A Saugier-Veber Pascale P Frébourg Thierry T Knebelmann Bertrand B Bekri Soumeya S

Molecular genetics & genomic medicine 20170516 4

<h4>Background</h4>Cystinuria is an autosomal recessive disorder of dibasic amino acid transport in the kidney and the intestine leading to increased urinary cystine excretion and nephrolithiasis. Two genes, <i>SLC3A1</i> and <i>SLC7A9</i>, coding respectively for rBAT and b0,+AT, account for the genetic basis of cystinuria.<h4>Methods</h4>This study reports the clinical and molecular characterization of a French cohort including 112 cystinuria patients and 25 relatives from 99 families. Molecul ...[more]

PMID: 28717662

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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

Clinical and molecular characterization of cystinuria in a French cohort: relevance of assessing large-scale rearrangements and splicing variants.

Publications

Clinical and molecular characterization of cystinuria in a French cohort: relevance of assessing large-scale rearrangements and splicing variants.

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