Pitfalls in the interpretation of
            <i>CFTR</i>
            variants in the context of incidental findings

Boussaroque, Agathe; Bergougnoux, Anne; Raynal, Caroline; Audrézet, Marie-Pierre; Sasorith, Souphatta; Férec, Claude; Bienvenu, Thierry; Girodon, Emmanuelle

doi:10.1002/humu.23884

Cited by 9 publications

(6 citation statements)

References 23 publications

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“…In particular, the class of CFTR-RD-causing variants is not referenced in CFTR2 and variants classified as CFTR-RD in CFTR-France may be found either as VVCC or not CF-causing in CFTR2. Other general databases such as ClinVar [42], and Human Gene Mutation Database ® [43], also provide clinical information and variant classification, mostly based on literature data, but numerous variants have been overclassified as "pathogenic" [44]. +: data available in the locus specific databases; -: data unavailable in the locus specific databases; LOVD: Leiden Open Variant Database [45]; NBS: newborn screening.…”

Section: Population Data (Clinical)mentioning

confidence: 99%

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Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges

Bienvenu

Lopez

Girodon

2020

Genes

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Identification of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and its numerous variants opened the way to fantastic breakthroughs in diagnosis, research and treatment of cystic fibrosis (CF). The current and future challenges of molecular diagnosis of CF and CFTR-related disorders and of genetic counseling are here reviewed. Technological advances have enabled to make a diagnosis of CF with a sensitivity of 99% by using next generation sequencing in a single step. The detection of heretofore unidentified variants and ethnic-specific variants remains challenging, especially for newborn screening (NBS), CF carrier testing and genotype-guided therapy. Among the criteria for assessing the impact of variants, population genetics data are insufficiently taken into account and the penetrance of CF associated with CFTR variants remains poorly known. The huge diversity of diagnostic and genetic counseling indications for CFTR studies makes assessment of variant disease-liability critical. This is especially discussed in the perspective of wide genome analyses for NBS and CF carrier screening in the general population, as future challenges.

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Section: Population Data (Clinical)mentioning

confidence: 99%

“…With the advent of wide genome analysis, aggregators that combine multiple evaluation tools have been implemented, such as Varsome [47] or Intervar [48]. They may be of help but exhibit significant limitations for CFTR variants, displaying a high degree of uncertainty for numerous variants [44].…”

Section: Computational and Predictive Datamentioning

confidence: 99%

Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges

Bienvenu

Lopez

Girodon

2020

Genes

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“…Updated information should be provided to families as knowledge evolves on variant pathogenicity, but such recalls could also generate anxiety. Population genetics data should not be neglected, as it has been shown that a number of variants classified as VUS or VVCC in CFTR2 actually have a frequency in the general population that argues against a severe impact, as for c.2620-26A>G, R74W, R117H, I556V, or D1270N [65]. The risk is to consider neonates as carriers of a CF-causing variant and to offer inappropriate genetic counseling and testing in the family, and eventually inappropriate prenatal diagnosis.…”

Section: Carrier Detection and Genetic Counselingmentioning

confidence: 99%

The Role of Extended CFTR Gene Sequencing in Newborn Screening for Cystic Fibrosis

Bergougnoux

Lopez

Girodon

2020

IJNS

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There has been considerable progress in the implementation of newborn screening (NBS) programs for cystic fibrosis (CF), with DNA analysis being part of an increasing number of strategies. Thanks to advances in genomic sequencing technologies, CFTR-extended genetic analysis (EGA) by sequencing its coding regions has become affordable and has already been included as part of a limited number of core NBS programs, to the benefit of admixed populations. Based on results analysis of existing programs, the values and challenges of EGA are reviewed in the perspective of its implementation on a larger scale. Sensitivity would be increased at best by using EGA as a second tier, but this could be at the expense of positive predictive value, which improves, however, if EGA is applied after testing a variant panel. The increased detection of babies with an inconclusive diagnosis has proved to be a major drawback in programs using EGA. The lack of knowledge on pathogenicity and penetrance associated with numerous variants hinders the introduction of EGA as a second tier, but EGA with filtering for all known CF variants with full penetrance could be a solution. The issue of incomplete knowledge is a real challenge in terms of the implemention of NBS extended to many genetic diseases.

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“…The copyright holder for this preprint this version posted August 13, 2021. ; https://doi.org/10.1101/2021.08. 13.453827 doi: bioRxiv preprint…”

Section: Introductionmentioning

confidence: 99%

“…STXBP1 has a wide range of functions, including the transport of Syntaxin 1A (STX1A), a vesicular release protein, from the soma to the synapse via binding at STX1A's Habc subdomain 12 . STXBP1 also enables Syntaxin to form SNARES at the synaptic terminal and fuse with the membrane for vesicular release via binding at a second site, the N-terminal [13][14][15][16][17][18] (Figure 1B). Models of STXBP1 dysfunction exist across the entire spectrum of research animals and cell lines, including yeast, flies, worms, mice, HEK293 cell culture, and differentiated fibroblasts, underlining its importance.…”

mentioning

confidence: 99%

A Gene Replacement Humanization Platform for Rapid Functional Testing of Clinical Variants in Epilepsy-associatedSTXBP1

McCormick¹,

Brock²,

Wood

et al. 2021

Preprint

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Purpose: Functional evidence is a pillar of variant interpretation according to ACMG guidelines. Functional evidence can be obtained in a variety of models and assay systems, including patient-derived tissues and iPSCs, in vitro cellular assays, and in vivo assays. Here we evaluate the reliability and practicality of variant interpretation in the small animal model, C. elegans, through a series of experiments evaluating the function of syntaxin binding protein, STXBP1, a well-known causative gene for Early infantile epileptic encephalopathy 1 (EIEE1). Methods: Using CRISPR, we replaced the coding sequence for unc-18 with the coding sequence for the human ortholog STXBP1. Next, we used CRISPR to introduce precise point mutations in the human STXBP1 coding sequence, reflecting three clinical categories (benign, pathogenic, and variants of uncertain significance (VUS)). We quantified 26 features of the resulting worms movement to train Random Forest (RF) and Support Vector Machines (SVM) machine learning classifiers on known pathogenic and benign variants. We characterized the classifiers, and then used the behavioral data from the VUS-expressing animals to predict the categorization of the VUS. Results: Whereas knock-out worms without unc-18 are severely impaired in motor function, worms expressing STXBP1 in its place have restored motor function. We produced worms with STXBP1 variants previously classified by ACMG criteria, including 25 benign variants, 32 pathogenic, and 24 variants of uncertain significance (VUS). Using either SVM or RF classifiers, we were able to obtain a sensitivity of 0.84-0.97 on known benign and pathogenic strains. By comparing multiple ML classification methods, we were able to classify 9 of the VUS as functionally abnormal, suggesting that these VUS are likely to be pathogenic. Conclusions: We demonstrate that automated analysis of a small animal system is an effective, scalable, and fast way to understand functional consequences of variants in STXBP1, one of the most common causes of genetic epilepsies and neurodevelopmental disorders. Keywords: STXBP1, C. elegans, CRISPR, Unc-18

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Pitfalls in the interpretation of CFTR variants in the context of incidental findings

Abstract: Whole-exome/

Cited by 9 publications

References 23 publications

Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges

Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges

The Role of Extended CFTR Gene Sequencing in Newborn Screening for Cystic Fibrosis

A Gene Replacement Humanization Platform for Rapid Functional Testing of Clinical Variants in Epilepsy-associatedSTXBP1

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