Reclassifying inconclusive diagnosis after newborn screening for cystic fibrosis. Moving forward

Hatton, Aurélie; Bergougnoux, Anne; Zybert, K.; Chevalier, B.; Mesbahi, Myriam; Altéri, Jean Pierre; Walicka‐Serzysko, Katarzyna; Postek, Magdalena; Taulan, Magali; Edelman, Aleksander; Hinzpeter, Alexandre; Claustres, Mireille; Girodon, Emmanuelle; Raynal, Caroline; Sermet‐Gaudelus, Isabelle; Sands, Dorota

doi:10.1016/j.jcf.2021.12.010

Cited by 12 publications

(7 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our cohort the individual compound heterozygous for the S737F and dele22-24 variant, showed a reduced CFTR activity (10.1 ± 1.1 µA), which points towards a diagnosis of CFTR-RD, given that functional threshold for CFTR-RD seems to be between 10% and 30% of normal [ 21 , 22 ]. Higher total CFTR activity was found for the other 2 subjects, homozygous for the S737F variant (24.2 ± 3.6 µA) and heterozygous for the S737F (20.4 ± 3.8 µA).…”

Section: Discussionmentioning

confidence: 66%

Clinical Consequences and Functional Impact of the Rare S737F CFTR Variant and Its Responsiveness to CFTR Modulators

Terlizzi

Pesce

Capurro

et al. 2023

IJMS

View full text Add to dashboard Cite

S737F is a cystic fibrosis (CF) transmembrane conductance regulator (CFTR) missense variant. The aim of our study was to describe the clinical features of a cohort of individuals carrying this variant. In parallel, by exploiting ex vivo functional and molecular analyses on nasal epithelia derived from a subset of S737F carriers, we evaluated its functional impact on CFTR protein, as well as its responsiveness to CFTR modulators. We retrospectively collected clinical data of all individuals bearing at least one S737F CFTR variant and followed at the CF Centre of Tuscany region (Italy). Nasal brushing was performed in cooperating individuals. At study end clinical data were available for 10 subjects (mean age: 14 years; range 1–44 years; three adult individuals). Five asymptomatic subjects had CF, and two were CRMS/CFSPID, and three had an inconclusive diagnosis. Ex vivo analysis on nasal epithelia demonstrated different levels of CF activity. In particular, epithelia derived from asymptomatic CF subjects and from one of the subjects with inconclusive diagnosis showed reduced CFTR activity that could be rescued by treatment with CFTR modulators. On the contrary, in the epithelia derived from the other two individuals with an inconclusive diagnosis, the CFTR-mediated current was similar to that observed in epithelia derived from healthy donors. In vitro functional and biochemical analysis on S737F-CFTR expressed in immortalized bronchial cells highlighted a modest impairment of the channel activity, which was improved by treatment with ivacaftor alone or in combination with tezacaftor/elexacaftor. Our study provide evidence towards the evaluation of CFTR function on ex vivo nasal epithelial cell models as a new assay to help clinicians to classify individuals, in presence of discordance between clinical picture, sweat test, and genetic profile.

show abstract

Section: Discussionmentioning

confidence: 66%

Clinical Consequences and Functional Impact of the Rare S737F CFTR Variant and Its Responsiveness to CFTR Modulators

Terlizzi

Pesce

Capurro

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…D924N resides in the potentiator binding hotspot [ 35 , 36 ] and, according to clinical data, may cause pancreatic insufficiency but not lung disease [ 37 ]. M952T displays robust functional expression in vitro [ 38 ], and two patients with an M952T/F508del genotype exhibit normal chloride transport measured from intestinal mucosa [ 38 ]–suggesting this variant is likely not pathogenic, despite the AM prediction.…”

Section: Resultsmentioning

confidence: 99%

Benchmarking AlphaMissense pathogenicity predictions against cystic fibrosis variants

McDonald,

Oliver,

Schlebach

et al. 2024

PLoS ONE

View full text Add to dashboard Cite

Variants in the cystic fibrosis transmembrane conductance regulator gene (CFTR) result in cystic fibrosis–a lethal autosomal recessive disorder. Missense variants that alter a single amino acid in the CFTR protein are among the most common cystic fibrosis variants, yet tools for accurately predicting molecular consequences of missense variants have been limited to date. AlphaMissense (AM) is a new technology that predicts the pathogenicity of missense variants based on dual learned protein structure and evolutionary features. Here, we evaluated the ability of AM to predict the pathogenicity of CFTR missense variants. AM predicted a high pathogenicity for CFTR residues overall, resulting in a high false positive rate and fair classification performance on CF variants from the CFTR2.org database. AM pathogenicity score correlated modestly with pathogenicity metrics from persons with CF including sweat chloride level, pancreatic insufficiency rate, and Pseudomonas aeruginosa infection rate. Correlation was also modest with CFTR trafficking and folding competency in vitro. By contrast, the AM score correlated well with CFTR channel function in vitro–demonstrating the dual structure and evolutionary training approach learns important functional information despite lacking such data during training. Different performance across metrics indicated AM may determine if polymorphisms in CFTR are recessive CF variants yet cannot differentiate mechanistic effects or the nature of pathophysiology. Finally, AM predictions offered limited utility to inform on the pharmacological response of CF variants i.e., theratype. Development of new approaches to differentiate the biochemical and pharmacological properties of CFTR variants is therefore still needed to refine the targeting of emerging precision CF therapeutics.

show abstract

“…Based on these findings, the authors concluded that children with CRMS/CFSPID are at risk of reclassification to CF, although genotype alone cannot determine risk. Functional assays were explored in 23 children with CRMS/CFSPID with one CF‐causing variant and one variant of varying clinical consequence, identifying intestinal current measurements (ICM) or nasal potential difference (NPD) as potentially useful to help predict future reclassification 14 …”

Section: Crms/cfspidmentioning

confidence: 99%

“…Functional assays were explored in 23 children with CRMS/CFSPID with one CFcausing variant and one variant of varying clinical consequence, identifying intestinal current measurements (ICM) or nasal potential difference (NPD) as potentially useful to help predict future reclassification. 14 Functional assays may be of benefit in CFTR-related disorders (CFTR-RD). Development of symptoms consistent with CF in children with CRMS/CFSPID or children who did not undergo NBS, and do not fulfill the diagnostic criteria for CF are classified as CFTR-RD.…”

Section: Crms/cfspidmentioning

confidence: 99%

Cystic fibrosis year in review 2022

Kim,

Lyman,

Savant

2023

Pediatric Pulmonology

View full text Add to dashboard Cite

Remarkable medical advancements have been made for people with cystic fibrosis (CF) in recent years, with an abundance of research continuing to be conducted worldwide. With concern for limitations in access to highly effective CFTR modulators, as well as the recent Coronavirus Disease‐19 pandemic, there has been a consistent effort to understand and improve CF screening, disease burden, diagnosis, and management. Our aim in this review is to present articles from 2022 with an emphasis on clinically relevant studies. We hope this will serve as a broad overview of the research published in the past year.

show abstract

Reclassifying inconclusive diagnosis after newborn screening for cystic fibrosis. Moving forward

Cited by 12 publications

References 41 publications

Clinical Consequences and Functional Impact of the Rare S737F CFTR Variant and Its Responsiveness to CFTR Modulators

Clinical Consequences and Functional Impact of the Rare S737F CFTR Variant and Its Responsiveness to CFTR Modulators

Benchmarking AlphaMissense pathogenicity predictions against cystic fibrosis variants

Cystic fibrosis year in review 2022

Contact Info

Product

Resources

About