Small-scale high-throughput sequencing–based identification of new therapeutic tools in cystic fibrosis

Bonini, Jennifer; Varilh, Jessica; Raynal, Caroline; Thèze, C.; Beyne, Emmanuelle; Audrézet, Marie-Pierre; Férec, Claude; Bienvenu, Thierry; Girodon, Emmanuelle; Tuffery‐Giraud, Sylvie; Georges, Marie des; Claustres, Mireille; Taulan, Magali

doi:10.1038/gim.2014.194

Cited by 31 publications

(39 citation statements)

References 33 publications

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“…Our unbiased screening approach revealed some unexpected genotype-phenotype correlations and allowed us to make diagnoses in genes which were previously investigated. As a first example, a heterozygous frameshift mutation in exon 8 of SYPC3 escaping nonsensemediated RNA decay and leading to a truncated, but stable protein was previously described in two unrelated patients with azoospermia as a result of meiotic arrest (Miyamoto et al, 2003 Bonini et al, 2015;Trujillano, et al, 2015), most clinics still apply traditional mutation screening to detect only the most common mutations across local populations. Because of this, screening for CFTR mutations in CBAVD patients regularly leads to the identification of only one affected allele because the second change is often a rare mutation or a genomic rearrangement affecting the CFTR gene (Giuliani et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia

et al. 2017

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Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY), and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here, we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified five patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11-17 patients (1%-1.5%), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared with currently used methods.

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Section: Discussionmentioning

confidence: 99%

Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia

et al. 2017

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“…About 11% of mutations-causing CF occur by incorrect splicing and this approach has shown to modulate the splicing and restore normal full-length CFTR transcript, as well as rescue functional CFTR protein (Bonini et al, 2015; Igreja et al, 2016). …”

Section: Classes Of Cftr Mutations and Cftr Modulatorsmentioning

confidence: 99%

CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis

2016

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Cystic fibrosis (CF) is the most common life-threatening monogenic disease aﬄicting Caucasian people. It affects the respiratory, gastrointestinal, glandular and reproductive systems. The major cause of morbidity and mortality in CF is the respiratory disorder caused by a vicious cycle of obstruction of the airways, inflammation and infection that leads to epithelial damage, tissue remodeling and end-stage lung disease. Over the past decades, life expectancy of CF patients has increased due to early diagnosis and improved treatments; however, these patients still present limited quality of life. Many attempts have been made to rescue CF transmembrane conductance regulator (CFTR) expression, function and stability, thereby overcoming the molecular basis of CF. Gene and protein variances caused by CFTR mutants lead to different CF phenotypes, which then require different treatments to quell the patients’ debilitating symptoms. In order to seek better approaches to treat CF patients and maximize therapeutic effects, CFTR mutants have been stratified into six groups (although several of these mutations present pleiotropic defects). The research with CFTR modulators (read-through agents, correctors, potentiators, stabilizers and amplifiers) has achieved remarkable progress, and these drugs are translating into pharmaceuticals and personalized treatments for CF patients. This review summarizes the main molecular and clinical features of CF, emphasizes the latest clinical trials using CFTR modulators, sheds light on the molecular mechanisms underlying these new and emerging treatments, and discusses the major breakthroughs and challenges to treating all CF patients.

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“…Targeted re-sequencing isolates genomic regions of interest in a sample library, allowing to focus efficiently and cost-effectively on a small subset of the genome, such as an exome, a particular chromosome, a set of genes or a region of interest such as a whole gene. Two main strategies can be envisioned: capture [16,17] or amplification relevant genomic DNA [18][19][20] as shown in Table 3.…”

Section: Target Enrichmentmentioning

confidence: 99%

“…In literature, three studies reported NGS CFTR sequencing (Table 4) on CF patients, CF carriers or controls samples [18,26,27]. Abou Tayoun and colleagues [26] first proposed a proof-of-concept for a 'CFTR exome' analysis by NGS on 79 samples.…”

Section: Indications and Choice Of Cftr Analysed Regionsmentioning

confidence: 99%

“…We proposed a complete CFTR gene sequencing of DNA samples from patients with a confirmed CF clinical diagnosis but with an incomplete genotype [18]. Although large unexplored intronic regions might contain few mutations (about 1%-3% of CF mutations), we identified a new pathogenic mutation, which creates a pseudo-exon (Table 4).…”

Section: Indications and Choice Of Cftr Analysed Regionsmentioning

confidence: 99%

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New Molecular Diagnosis Approaches — From the Identification of Mutations to their Characterization

Bergougnoux¹,

Taulan²,

Claustres³

et al. 2015

Cystic Fibrosis in the Light of New Research

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Small-scale high-throughput sequencing–based identification of new therapeutic tools in cystic fibrosis

Abstract: Our data confirm the importance of analyzing noncoding regions to find unidentified mutations, which is essential to designing targeted therapeutic approaches.

Cited by 31 publications

References 33 publications

Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia

Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia

CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis

New Molecular Diagnosis Approaches — From the Identification of Mutations to their Characterization

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