Multicenter validation study for the certification of a CFTR gene scanning method using next generation sequencing technology

Bergougnoux, Anne; D’Argenio, Valeria; Sollfrank, Stefanie; Verneau, F.; Telese, Antonella; Postiglione, Irene; Lackner, Karl J.; Claustres, Mireille; Castaldo, Giuseppe; Rossmann, Heidi; Salvatore, Francesco; Raynal, Caroline

doi:10.1515/cclm-2017-0553

Cited by 24 publications

(15 citation statements)

References 20 publications

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“…Similarly, four of the eight patients that we diagnosed as CF-SPID at the newborn period who evolved into CFTR-RD (# 1, 3, 4, 6 in Table 5 ) also had a ST < 30 mmol/L, a single variant after first level analysis, among which the D1152H in four cases [ 22 ] and the second variant with undefined phenotypic consequences, i.e., Q1476X, L997F (2 cases) and S1426 F, were revealed by sequencing. Therefore, gene sequencing, which today can be performed with costs comparable to those of commercial panels of variants [ 10 ], significantly increases the number of CF-SPID diagnosed, and also other studies suggest performing extended gene analysis in subjects with CF-SPID [ 8 ]. Consequently, it allows start a follow-up of such subjects aimed to early reveal cases that may evolve into CF or CFTR-RD.…”

Section: Discussionmentioning

confidence: 99%

“…The CFTR genotype was defined by the first level molecular analysis testing for 40 most frequent variants and for variants peculiar to Southern Italy. Thus, we performed the search for large gene deletions [ 9 ] and gene sequencing [ 10 ] in all cases that had: (i) a CFTR variant at the first level analysis; (ii) sweat chloride levels > 30 ng/mL. To define the effect of CFTR variants we referred to the CFTR 2 and to the French CFTR databases [ 11 , 12 ].…”

Section: Methodsmentioning

confidence: 99%

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Cystic Fibrosis-Screening Positive Inconclusive Diagnosis: Newborn Screening and Long-Term Follow-Up Permits to Early Identify Patients with CFTR-Related Disorders

et al. 2020

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Background: Newborn screening (NBS) early-identifies cystic fibrosis (CF), but in CF-screening positive inconclusive diagnosis (CF-SPID) the results of immunoreactive trypsinogen (IRT), molecular analysis and sweat test (ST) are discordant. A percentage of CF-SPID evolves to CF, but data on long-term monitoring are lacking. We describe the follow-up of all CF and CF-SPID identified between 2008 and 2019. Methods: NBS was performed by IRT followed by molecular analysis and ST between 2008 and 2014; double IRT followed by molecular analysis and ST after 2014. Results: NBS revealed 47 CF and 99 CF-SPID newborn, a ratio 1:2.1—the highest reported so far. This depends on the identification by gene sequencing of the second variant with undefined effect in 40 CF-SPID that otherwise would have been defined as carriers. Clinical complications and pulmonary infections occurred more frequently among CF patients than among CF-SPID. Two CF-SPID cases evolved to CF (at two years), while eight evolved to CFTR-related disorders (CFTR-RD), between one and eight years, with bronchiectasis (two), recurrent pneumonia (four, two with sinonasal complications), recurrent pancreatitis (two). No clinical, biochemical or imaging data predicted the evolution. Conclusion: Gene sequencing within the NBS reveals a higher number of CF-SPID and we first describe an approach to early identify CFTR-RD, with relevant impact on their outcome.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Cystic Fibrosis-Screening Positive Inconclusive Diagnosis: Newborn Screening and Long-Term Follow-Up Permits to Early Identify Patients with CFTR-Related Disorders

et al. 2020

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“…It is also possible that traditional technologies did not enable prior detection of these variants. High-throughput NGS technologies have greatly improved the possibility of identifying rare CFTR variants, and of thus further elucidating the genetic heterogeneity of CF [9, 17, 23]. These approaches also dramatically increase the possibility of identifying novel and de novo variants.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing for identifying a novel/de novo pathogenic variant in a Mexican patient with cystic fibrosis: a case report

et al. 2019

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Background Mexico is among the countries showing the highest heterogeneity of CFTR variants. However, no de novo variants have previously been reported in Mexican patients with cystic fibrosis (CF). Case presentation Here, we report the first case of a novel/de novo variant in a Mexican patient with CF. Our patient was an 8-year-old male who had exhibited the clinical onset of CF at one month of age, with steatorrhea, malabsorption, poor weight gain, anemia, and recurrent respiratory tract infections. Complete sequencing of the CFTR gene by next generation sequencing (NGS) revealed two different variants in trans , including the previously reported CF-causing variant c.3266G > A (p.Trp1089*, W1089*), that was inherited from the mother, and the novel/de novo CFTR variant c.1762G > T (p.Glu588*). Conclusion Our results demonstrate the efficiency of targeted NGS for making a rapid and precise diagnosis in patients with clinically suspected CF. This method can enable the provision of accurate genetic counselling, and improve our understanding of the molecular basis of genetic diseases.

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“…In all patients, the CFTR genotype was defined by screening a panel of the most frequent point mutations 42 and gene rearrangements 43 . Moreover, CFTR Sanger gene sequencing 44 or NGS 45 was performed when mutations were not detected in one or both alleles by first-level analysis. Furthermore, we analysed 7 intragenic CFTR short tandem repeats 46 to verify that both members of three sibling-pairs carrying only one known mutation had the same CFTR genotype.…”

Section: Methodsmentioning

confidence: 99%

TAS2R38 is a novel modifier gene in patients with cystic fibrosis

Castaldo

Cernera

Iacotucci

et al. 2020

Sci Rep

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The clinical manifestation of cystic fibrosis (CF) is heterogeneous also in patients with the same cystic fibrosis transmembrane regulator (CFTR) genotype and in affected sibling pairs. Other genes, inherited independently of CFTR, may modulate the clinical manifestation and complications of patients with CF, including the severity of chronic sinonasal disease and the occurrence of chronic Pseudomonas aeruginosa colonization. The T2R38 gene encodes a taste receptor and recently its functionality was related to the occurrence of sinonasal diseases and upper respiratory infections. We assessed the T2R38 genotype in 210 patients with CF and in 95 controls, relating the genotype to the severity of sinonasal disease and to the occurrence of P. aeruginosa pulmonary colonization. The frequency of the PAV allele i.e., the allele associated with the high functionality of the T2R38 protein, was significantly lower in i) CF patients with nasal polyposis requiring surgery, especially in patients who developed the complication before 14 years of age; and ii) in CF patients with chronic pulmonary colonization by P. aeruginosa, especially in patients who were colonized before 14 years of age, than in control subjects. These data suggest a role for T2R38 as a novel modifier gene of sinonasal disease severity and of pulmonary P. aeruginosa colonization in patients with CF.

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Multicenter validation study for the certification of a CFTR gene scanning method using next generation sequencing technology

Cited by 24 publications

References 20 publications

Cystic Fibrosis-Screening Positive Inconclusive Diagnosis: Newborn Screening and Long-Term Follow-Up Permits to Early Identify Patients with CFTR-Related Disorders

Cystic Fibrosis-Screening Positive Inconclusive Diagnosis: Newborn Screening and Long-Term Follow-Up Permits to Early Identify Patients with CFTR-Related Disorders

Next-generation sequencing for identifying a novel/de novo pathogenic variant in a Mexican patient with cystic fibrosis: a case report

TAS2R38 is a novel modifier gene in patients with cystic fibrosis

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