Identification of a novel duplication CFTRdup2 and functional impact of large rearrangements identified in the CFTR gene

Taulan, Magali; Viart, Victoria; Thèze, C.; Guittard, Caroline; Altiéri, Jean-Pierre; Templin, Carine; Mély, Laurent; Claustres, Mireille; Georges, Marie des

doi:10.1016/j.gene.2012.03.043

Cited by 10 publications

(10 citation statements)

References 17 publications

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“…It has been observed that either duplications or deletions of exon 2 reduce the amount of the produced protein, affecting both the process of transcription and transcript stability. In the case of duplications, the production of a more glycosylated protein was also observed (Taulan, 2012). The patient FC337 that presented this duplication, died at the age of 11 years.…”

Section: Discussionmentioning

confidence: 95%

“…However, large rearrangements may occur, such as large duplications or deletions, many already described in the CFMDB; these alterations are not detected by traditional screening methods and require special techniques for their observation (Férec et al, ). Currently, several methods are available for the screening of genetic rearrangements, such as Multiplex Ligation‐dependent Probe Amplification (MLPA) (Schrijver, Rappahahn, Pique, Kharrazi, & Wong, ; Taulan et al, ). This methodology has been widely applied in a variety of clinical situations and investigations to detect gains or losses of genomic sequences.…”

Section: Introductionmentioning

confidence: 99%

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Identification of a novel large deletion and other copy number variations in theCFTRgene in patients with Cystic Fibrosis from a multiethnic population

Martins

Campos

Moreira

et al. 2019

Molec Gen & Gen Med

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Background Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR ). There are over 2000 different pathogenic and non‐pathogenic variants described in association with a broad clinical heterogeneity. The most common types of mutations in this gene are single nucleotide substitutions or small deletions and insertions. However, large rearrangements, such as large duplications or deletions, are also a possible cause of CF; these variations are rarely tested in routine screenings, and much of them remain unidentified in some populations, especially those with high ethnic heterogeneity. Methods The present study utilized the Multiplex Ligation‐dependent Probe Amplification (MLPA) technique for the detection of duplications and deletions in 165 CF patients from the Rio de Janeiro State (Brazil), which after extensive mutational screening, still exhibited one or two unidentified CF alleles. Results Five patients with alterations in MLPA signals were detected. After validation, we identified three copy number variations, one large duplication (CFTRdup2‐3) and two large deletions (CFTRdel25‐26 and CFTRdel25‐27‐CTTNBP2). Two detected deletions were not validated. They were false positives caused by a small deletion of 18 base pairs (232del18) and a point mutation (S168L) in the probe binding site. Conclusion Our results highlight the importance of screening for large rearrangements in CF cases with no or only one CFTR mutation defined.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Identification of a novel large deletion and other copy number variations in theCFTRgene in patients with Cystic Fibrosis from a multiethnic population

Martins

Campos

Moreira

et al. 2019

Molec Gen & Gen Med

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“…In the past, large deletions and gross rearrangements in the CFTR gene would only be detected through the appearance of UPD inheritance and changes on Southern blots [12, 13]. With the recent development of modern techniques such as MLPA, array-CGH, and fluorescent multiplex PCR more genomic aberrations such as large deletions and gross rearrangements are a lot easier to identify [6, 7, 12, 14–16]. …”

Section: Discussionmentioning

confidence: 99%

Apparent Homozygosity of p.Phe508del inCFTRdue to a Large Gene Deletion of Exons 4–11

Neocleous

Yiallouros

Tanteles

et al. 2014

Case Reports in Genetics

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We report a classic cystic fibrosis (CF) boy with a large deletion of exons 4–11 in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on one allele and p.Phe508del in exon 10 on the second allele. Both parents of Georgian and Ukrainian background had no personal or family history of the disease. The initial molecular diagnostic investigation identified the patient as homozygous for the p.Phe508del and not compatible with his parent's genetic status. The possibility of nonpaternity or uniparental disomy (UPD7) was investigated and excluded using microsatellite analysis of highly polymorphic markers on chromosome 7. Array-CGH was also performed on the patient and revealed a male profile with a subtle deletion within the CFTR gene on the long arm (q-arm) of chromosome 7 (7q31.2). The deletion was confirmed by MLPA extending from probe L02380 to probe L14978 (28.7 kb) and that was inherited from his father, while p.PheF508del was inherited from his mother. These data highlight the need for additional testing for large deletions in patients with apparent homozygosity for a mutated CFTR allele that do not match the carrier status of the parents. Not testing can lead to misdiagnosis and misinterpretation of mutation carrier status and the expected penetrance of the disorder.

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“…As an example, Taulan et al. (), using a combination of functional assays, showed that in‐frame copy‐number variations of exon 2 (deletion or duplication), not only decreased the quantity of mature CFTR protein, but also affected mRNA levels. Genomic rearrangements in CFTR have been associated with diverse mutational mechanisms, essentially mediated by nonhomologous recombination (Audrezet et al., ; Férec et al., ; Niel et al., ).…”

Section: Current Content Of Cftr‐francementioning

confidence: 99%

CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rareCFTRvariants

et al. 2017

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Most of the 2,000 variants identified in the CFTR (cystic fibrosis transmembrane regulator) gene are rare or private. Their interpretation is hampered by the lack of available data and resources, making patient care and genetic counseling challenging. We developed a patient-based database dedicated to the annotations of rare CFTR variants in the context of their cis- and trans-allelic combinations. Based on almost 30 years of experience of CFTR testing, CFTR-France (https://cftr.iurc.montp.inserm.fr/cftr) currently compiles 16,819 variant records from 4,615 individuals with cystic fibrosis (CF) or CFTR-RD (related disorders), fetuses with ultrasound bowel anomalies, newborns awaiting clinical diagnosis, and asymptomatic compound heterozygotes. For each of the 736 different variants reported in the database, patient characteristics and genetic information (other variations in cis or in trans) have been thoroughly checked by a dedicated curator. Combining updated clinical, epidemiological, in silico, or in vitro functional data helps to the interpretation of unclassified and the reassessment of misclassified variants. This comprehensive CFTR database is now an invaluable tool for diagnostic laboratories gathering information on rare variants, especially in the context of genetic counseling, prenatal and preimplantation genetic diagnosis. CFTR-France is thus highly complementary to the international database CFTR2 focused so far on the most common CF-causing alleles.

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Identification of a novel duplication CFTRdup2 and functional impact of large rearrangements identified in the CFTR gene

Cited by 10 publications

References 17 publications

Identification of a novel large deletion and other copy number variations in theCFTRgene in patients with Cystic Fibrosis from a multiethnic population

Identification of a novel large deletion and other copy number variations in theCFTRgene in patients with Cystic Fibrosis from a multiethnic population

Apparent Homozygosity of p.Phe508del inCFTRdue to a Large Gene Deletion of Exons 4–11

CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rareCFTRvariants

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