Cystic fibrosis in Tuscany: evolution of newborn screening strategies over time to the present

Abstract Background Cystic fibrosis (CF) is a life-threatening disease affecting about 1:3000 newborns in Caucasian populations. The introduction of newborn screening for cystic fibrosis (CF NBS) has improved the clinical outcomes of individuals with CF through early diagnosis and early treatment. NBS strategies have been implemented over time. CF NBS was introduced extensively in 1984 in Tuscany, a region with 3.7 million people, characterized by a high allelic heterogeneity of CFTR gene. Aim and methods The aim of the study is to present the results from 34 years (1984–2018) of CF NBS, retrospectively evaluating the sensitivity, specificity and predictive values of the tests. In particular, we studied the impact of the introduction of DNA molecular analysis in NBS in a region with high allelic heterogeneity, such as Tuscany. Results Over these 34 years, 919,520 neonates were screened, using four different NBS strategies. From 1984 to 1991, CF NBS was performed by the determination of albumin on dried meconium (sensitivity 68.75%; specificity 99.82%). Subsequently, the analysis of immunoreactive trypsinogen on a blood spot was adopted as CF NBS protocol (sensitivity 83.33%; specificity 99.77%). From 1992 to 2010, this strategy was associated with lactase meconium dosage: IRT1/IRT2 + LACT protocol (sensitivity 87.50%; specificity 99.82%). From 2011, when the existing algorithm was integrated by analysis of CF causing variants of the CFTR gene (IRT1/IRT2 + LACT + IRT1/DNA protocol), a substantial improvement in sensitivity was seen (senisitivity 96.15%; specificity 99.75%). Other improved parameters with DNA analysis in the NBS programme, compared with the previous method, were the diagnosis time (52 days vs. 38 days) and the recall rate (0.58 to 0.38%). Conclusion The inclusion of DNA analysis in the NBS was a fundamental step in improving sensitivity, even in a region with high allelic variability.

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The Impact of the CFTR Gene Discovery on Cystic Fibrosis Diagnosis, Counseling, and Preventive Therapy

Genes ◽

10.3390/genes11040401 ◽

2020 ◽

Vol 11 (4) ◽

pp. 401 ◽

Cited By ~ 3

Author(s):

Philip M. Farrell ◽

Michael J. Rock ◽

Mei W. Baker

Keyword(s):

Cystic Fibrosis ◽

Dna Analysis ◽

Preventive Therapy ◽

Added Value ◽

Cftr Gene ◽

Optimal Size ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Scientific Advance ◽

The Impact

Discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was the long-awaited scientific advance that dramatically improved the diagnosis and treatment of cystic fibrosis (CF). The combination of a first-tier biomarker, immunoreactive trypsinogen (IRT), and, if high, DNA analysis for CF-causing variants, has enabled regions where CF is prevalent to screen neonates and achieve diagnoses within 1–2 weeks of birth when most patients are asymptomatic. In addition, IRT/DNA (CFTR) screening protocols simultaneously contribute important genetic data to determine genotype, prognosticate, and plan preventive therapies such as CFTR modulator selection. As the genomics era proceeds with affordable biotechnologies, the potential added value of whole genome sequencing will probably enhance personalized, precision care that can begin during infancy. Issues remain, however, about the optimal size of CFTR panels in genetically diverse regions and how best to deal with incidental findings. Because prospects for a primary DNA screening test are on the horizon, the debate about detecting heterozygote carriers will likely intensify, especially as we learn more about this relatively common genotype. Perhaps, at that time, concerns about CF heterozygote carrier detection will subside, and it will become recognized as beneficial. We share new perspectives on that issue in this article.

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

International Journal of Neonatal Screening ◽

10.3390/ijns6010023 ◽

2020 ◽

Vol 6 (1) ◽

pp. 23 ◽

Cited By ~ 2

Author(s):

Anne Bergougnoux ◽

Maureen Lopez ◽

Emmanuelle Girodon

Keyword(s):

Cystic Fibrosis ◽

Newborn Screening ◽

Dna Analysis ◽

Genetic Diseases ◽

Major Drawback ◽

Coding Regions ◽

Sequencing Technologies ◽

Second Tier ◽

Real Challenge

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 impact of newborn screening and earlier intervention on the clinical course of cystic fibrosis

Paediatric Respiratory Reviews ◽

10.1016/j.prrv.2012.05.003 ◽

2012 ◽

Vol 13 (4) ◽

pp. 220-225 ◽

Cited By ~ 34

Author(s):

F. Nicole Dijk ◽

Dominic A. Fitzgerald

Keyword(s):

Cystic Fibrosis ◽

Newborn Screening ◽

Clinical Course ◽

The Impact

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Cystic fibrosis newborn screening: outcome of infants with normal sweat tests

Archives of Disease in Childhood ◽

10.1136/archdischild-2017-313290 ◽

2017 ◽

Vol 103 (8) ◽

pp. 753-756 ◽

Cited By ~ 6

Author(s):

Claire Edmondson ◽

Christopher Grime ◽

Ammani Prasad ◽

Jacqui Cowlard ◽

Chinedu E C Nwokoro ◽

...

Keyword(s):

Cystic Fibrosis ◽

Newborn Screening ◽

Genome Sequencing ◽

Dna Analysis ◽

Gene Mutations ◽

High Serum ◽

Sweat Test ◽

Sweat Chloride ◽

South East England

Newborn babies positively screened for cystic fibrosis (CF) (high serum immunoreactive trypsin (IRT) with DNA analysis) are referred for a diagnostic sweat test, which may be normal (sweat chloride <30 mmol/L). Unless two gene mutations are identified during Newborn screening (NBS), the babies are discharged from follow-up. We wished to check that none had subsequently developed symptoms suggestive of CF. We retrospectively reviewed patient notes and contacted general practitioners of all babies with a negative sweat test, conducted in one of the four paediatric specialist CF centres in London, over the first 6 years of screening in South East England.Of 511 babies referred, 95 (19%) had a normal sweat test. Five (5%) had CF diagnosed genetically, two of them on extended genome sequencing after clinical suspicion. Eleven (12%) were designated as CF screen positive inconclusive diagnosis (CFSPID); one of the five CF children was originally designated as CFSPID. Seventy-nine (83%) were assumed to be false-positive cases and discharged; follow-up data were available for 51/79 (65%); 32/51 (63%) had no health issues, 19/51 (37%) had other significant non-CF pathology.These results are reassuring in that within the limitations of those lost to follow-up, CF symptoms have not emerged in the discharged children. The high non-CF morbidity in these children may relate to known causes of high IRT at birth. Clinicians need to be aware that a child can have CF despite a normal sweat test following NBS, and if symptoms suggest the diagnosis, further testing, including extended genome sequencing, is required.

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The impact of a national population carrier screening program on cystic fibrosis birth rate and age at diagnosis: Implications for newborn screening

Journal of Cystic Fibrosis ◽

10.1016/j.jcf.2015.08.007 ◽

2016 ◽

Vol 15 (4) ◽

pp. 460-466 ◽

Cited By ~ 18

Author(s):

Patrick Stafler ◽

Meir Mei-Zahav ◽

Michael Wilschanski ◽

Huda Mussaffi ◽

Ori Efrati ◽

...

Keyword(s):

Cystic Fibrosis ◽

Newborn Screening ◽

Birth Rate ◽

Screening Program ◽

Carrier Screening ◽

Age At Diagnosis ◽

National Population ◽

The Impact

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Combining Immunoreactive Trypsinogen and Pancreatitis-Associated Protein Assays, a Method of Newborn Screening for Cystic Fibrosis that Avoids DNA Analysis

The Journal of Pediatrics ◽

10.1016/j.jpeds.2005.05.017 ◽

2005 ◽

Vol 147 (3) ◽

pp. 302-305 ◽

Cited By ~ 49

Author(s):

Jacques Sarles ◽

Patrice Berthézène ◽

Christian Le Louarn ◽

Claude Somma ◽

Jean-Marc Perini ◽

...

Keyword(s):

Cystic Fibrosis ◽

Newborn Screening ◽

Dna Analysis ◽

Protein Assays ◽

Pancreatitis Associated Protein ◽

Immunoreactive Trypsinogen

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Investigating CFTR gene variations in patient groups with positive newborn screening test results and preliminary clinical diagnosis of cystic fibrosis in the eastern anatolia region of Turkey

Medicine Science | International Medical Journal ◽

10.5455/medscience.2020.10.228 ◽

2021 ◽

Vol 10 (2) ◽

pp. 293

Author(s):

Ayberk Turkyilmaz ◽

Oguzhan Yarali

Keyword(s):

Cystic Fibrosis ◽

Newborn Screening ◽

Clinical Diagnosis ◽

Screening Test ◽

Cftr Gene ◽

Eastern Anatolia ◽

Test Results ◽

Patient Groups

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The Changing Epidemiology of Cystic Fibrosis: Incidence, Survival and Impact of the CFTR Gene Discovery

Genes ◽

10.3390/genes11060589 ◽

2020 ◽

Vol 11 (6) ◽

pp. 589 ◽

Cited By ~ 4

Author(s):

Virginie Scotet ◽

Carine L’Hostis ◽

Claude Férec

Keyword(s):

Cystic Fibrosis ◽

Cftr Gene ◽

The Past ◽

Responsible Gene ◽

Family Testing ◽

The Face ◽

Serious Disease ◽

Molecular Bases ◽

The Impact ◽

Clinical Advances

Significant advances in the management of cystic fibrosis (CF) in recent decades have dramatically changed the epidemiology and prognosis of this serious disease, which is no longer an exclusively pediatric disease. This paper aims to review the changes in the incidence and survival of CF and to assess the impact of the discovery of the responsible gene (the CFTR gene) on these changes. The incidence of CF appears to be decreasing in most countries and patient survival, which can be monitored by various indicators, has improved substantially, with an estimated median age of survival of approximately50 years today. Cloning of the CFTR gene 30 years ago and efforts to identify its many mutations have greatly improved the management of CF. Implementation of genetic screening policies has enabled earlier diagnosis (via newborn screening), in addition to prevention within families or in the general population in some areas (via prenatal diagnosis, family testing or population carrier screening). In the past decade, in-depth knowledge of the molecular bases of CF has also enabled the emergence of CFTR modulator therapies which have led to major clinical advances in the treatment of CF. All of these phenomena have contributed to changing the face of CF. The advent of targeted therapies has paved the way for precision medicine and is expected to further improve survival in the coming years.

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