A recurrent deep-intronic splicing CF mutation emphasizes the importance of mRNA studies in clinical practice

Costa, Cathérine; Prulière-Escabasse, V.; Becdelièvre, Alix de; Gameiro, Christine; Golmard, Lisa; Guittard, Caroline; Bassinet, L.; Bienvenu, Thierry; Georges, Marie des; Epaud, Ralph; Bieth, Éric; Giurgea, Irina; Aissat, Abdel; Hinzpeter, Alexandre; Costes, Bruno; Fanen, Pascale; Goossens, Michel; Claustres, Mireille; Coste, A.; Girodon, Emmanuelle

doi:10.1016/j.jcf.2011.06.011

Cited by 19 publications

(14 citation statements)

References 8 publications

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“…Indeed, the proportion of alternative splicing for a given exon is an important parameter to consider [Spurdle et al, ], and can differ depending on cell type and tissue due to the differential expression of splicing factors [de la Grange et al, ]. The use of nasal epithelial cells of patients, the only validated model accessible to noninvasive collection, could provide a definite evaluation of the variant [Carvalho‐Oliveira et al, ; Costa et al, ]. In the same way, a supplementary blood sample for transcripts analysis is required for the classification of VUCS in BRCA 1 or BRCA2 gene [Houdayer et al, ; Spurdle et al, ].…”

Section: Discussionmentioning

confidence: 99%

A Classification Model Relative to Splicing for Variants of Unknown Clinical Significance: Application to theCFTRGene

et al. 2013

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Molecular diagnosis of cystic fibrosis and cystic fibrosis transmembrane regulator (CFTR)-related disorders led to the worldwide identification of nearly 1,900 sequence variations in the CFTR gene that consist mainly of private point mutations and small insertions/deletions. Establishing their effect on the function of the encoded protein and therefore their involvement in the disease is still challenging and directly impacts genetic counseling. In this context, we built a decision tree following the international guidelines for the classification of variants of unknown clinical significance (VUCS) in the CFTR gene specifically focused on their consequences on splicing. We applied general and specific criteria, including comprehensive review of literature and databases, familial genetics data, and thorough in silico studies. This model was tested on 15 intronic and exonic VUCS identified in our cohort. Six variants were classified as probably nonpathogenic considering their impact on splicing and eight as probably pathogenic, which include two apparent missense mutations. We assessed the validity of our method by performing minigenes studies and confirmed that 93% (14/15) were correctly classified. We provide in this study a high-performance method that can play a full role in interpreting the results of molecular diagnosis in emergency context, when functional studies are not achievable.

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Section: Discussionmentioning

confidence: 99%

A Classification Model Relative to Splicing for Variants of Unknown Clinical Significance: Application to theCFTRGene

et al. 2013

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“…Still, extensive screening of the CFTR gene coding regions may be negative, as was the case in our patient. In such situations, search for splicing defects in deep intronic regions, possibly by studying messenger RNA (mRNA) obtained from nasal epithelial cells, should be considered, as recently evidenced 6 7. In our patient, the recently described intron 7 c.870-1113_1110delGAAT mutation was specifically screened for and identified, which led to confirm the diagnosis of atypical CF.…”

Section: Discussionmentioning

confidence: 99%

“…It was first described in three Italian patients having classical CF. A French collaborative study in patients suspected to have CF and who had no or only one known CF mutation led to identify 17 patients presenting CF or a CFTR-related disorder 6. Fourteen of them were originated from France or Italy, and geographic origin was unknown for the others.…”

Section: Discussionmentioning

confidence: 99%

A rareCFTRintronic mutation related to a mild CF disease in a 12-year-old girl

Nathan¹,

Girodon²,

Clément³

et al. 2012

BMJ Case Reports

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We report the case of a 12-year-old girl with an allergic bronchopulmonary aspergillosis (ABPA), intermediate sweat chloride tests and one cystic fibrosis (CF)-causing mutation, p.Phe508del. After extensive screening of the CF transmembrane regulator (CFTR) gene, she finally was found to carry a rare deep intronic mutation (c.872-1110_1113delGAAT), which confirmed the atypical mild CF disease. Although a classical steroid treatment did not allow the healing of the ABPA, an omalizumab therapy led to a long-term recovery. This case emphasises the need to search for rareCFTRgene mutations as far as possible when a CF disease is evocated. Moreover, it also highlights that although omalizumab is not yet recognised as a classical ABPA treatment in CF, it should be considered as an alternative therapy in steroid-resistant patients.

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“…However, 1% to 5% of CF mutations remain unidentified after comprehensive gene analysis in patients with CF, 31 suggesting possible deep-intronic splicing mutations. 32,33 Although it is well established that CF lung disease may lead to bronchiectasis, there are no specific allelic mutations of the CFTR that are directly linked with the presence or severity of bronchiectasis. However, there are noted associations with CFTR mutations that result in more severe lung disease.…”

Section: Cystic Fibrosismentioning

confidence: 99%

Genetic Causes of Bronchiectasis

Gould

Freeman

Olivier

2012

Clinics in Chest Medicine

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A recurrent deep-intronic splicing CF mutation emphasizes the importance of mRNA studies in clinical practice

Abstract: c.870-1113_1110delGAAT should be considered as CF-causing with phenotype variability and overall delayed diagnosis. Its frequency highlights the potential of mRNA studies.

Cited by 19 publications

References 8 publications

A Classification Model Relative to Splicing for Variants of Unknown Clinical Significance: Application to theCFTRGene

A Classification Model Relative to Splicing for Variants of Unknown Clinical Significance: Application to theCFTRGene

A rareCFTRintronic mutation related to a mild CF disease in a 12-year-old girl

Genetic Causes of Bronchiectasis

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