Validation of CFTR intronic variants identified during cystic fibrosis population screening by a minigene splicing assay

Clinical Chemistry and Laboratory Medicine : CCLM
Gianpietro GiorgiLeonardo Salviati

Abstract

Cystic fibrosis, caused by mutations of the CFTR gene, is the most common autosomal recessive condition in the European population and there are specific screening programs aimed at investigating healthy carriers. They are usually articulated in two steps: initially individuals are screened with a panel of the 20-50 most common CFTR mutations; the second step is offered to partners of carriers who were found negative at the first test and consists in the analysis of the entire CFTR gene. This strategy provides high sensitivity, however, it often identifies novel variants (especially in introns) of unknown significance. Establishing the pathogenicity of these variants of the CFTR gene is not a simple task. We have examined five CFTR intronic variants of unclear significance (c.274-6T>C, c.744-6T>G, c.1117-64G>A, c.2620-26A>G, and c.3468+51C>A) using a functional splicing assay based on hybrid minigenes. Four out of five variants (including c.2620-26A>G which was previously reported as a possible splice-site mutation) did not alter the correct splicing of the minigene and are likely to be neutral polymorphisms, whereas c.744-6T>G caused complete skipping of CFTR exon 7 and should be therefore regarded as a pathogenic CFTR mutatio...Continue Reading

References

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Citations

Jan 16, 2016·International Journal of Molecular Sciences·Yoko NakajimaAndré B P Van Kuilenburg
Dec 15, 2016·European Journal of Human Genetics : EJHG·Matteo CassinaEva Trevisson
Apr 9, 2017·Gene·Rihab Kallel-BouattourHassen Hadj Kacem
Jun 12, 2020·Frontiers in Cell and Developmental Biology·Hecun ZouHong-Hao Zhou
Jun 9, 2021·Nature Communications·Dadi GaoSusan A Slaugenhaupt

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Methods Mentioned

BETA
PCR
electrophoresis
transfect

Software Mentioned

HSF
NetGene2
NNSplice
NetGene2 Splicing Finder )

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