A false positive newborn screening result due to a complex allele carrying two frequent CF-causing variants

Bergougnoux, Anne; Boureau-Wirth, Amandine; Rouzier, Cécile; Altiéri, Jean-Pierre; Verneau, F.; Larrieu, Lise; Kœnig, M.; Claustres, Mireille; Raynal, Caroline

doi:10.1016/j.jcf.2016.04.003

Cited by 15 publications

(14 citation statements)

References 20 publications

(22 reference statements)

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“…Most screened infants have little or no clinical manifestation of the disease, making sweat testing the main diagnostic tool to discriminate between children with and without CF [3,5,8,10]. A positive NBS result always requires a confirmatory sweat test, as there may be laboratory errors (mix-up of samples) or the two CFTR mutations detected in the genetic test are on the same allele [3,11]. The diagnostic algorithm of sweat testing is shown in Figure 1 [12].…”

Section: Sweat Test-the Gold Standard Confirmation Test Of a Positivementioning

confidence: 99%

Processing Newborn Bloodspot Screening Results for CF

Barben¹,

Chudleigh

2020

IJNS

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Every newborn bloodspot screening (NBS) result for cystic fibrosis (CF) consists of two parts: a screening part in the laboratory and a clinical part in a CF centre. When introducing an NBS programme, more attention is usually paid to the laboratory part, especially which algorithm is most suitable for the region or the country. However, the clinical part, how a positive screening result is processed, is often underestimated and can have great consequences for the affected child and their parents. A clear algorithm for the diagnostic part in CF centres is also important and influences the performance of a CF NBS programme. The processing of a positive screening result includes the initial information given to the parents, the invitation to the sweat test, what to do if a sweat test fails, information about the results of the sweat test, the inconclusive diagnosis and the carrier status, which is handled differently from country to country. The time until the definitive diagnosis and adequate information is given, is considered by the parents and the CF team as the most important factor. The communication of a positive NBS result is crucial. It is not a singular event but rather a process that includes ensuring the appropriate clinicians are aware of the result and that families are informed in the most efficient and effective manner to facilitate consistent and timely follow-up.

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Section: Sweat Test-the Gold Standard Confirmation Test Of a Positivementioning

confidence: 99%

Processing Newborn Bloodspot Screening Results for CF

Barben¹,

Chudleigh

2020

IJNS

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“…58 Clearly, the CF diagnosis is a serious one, and the sweat test provides an important safeguard to avoid mislabeling babies because of identity errors, or laboratory errors in IRT or DNA analysis. 59,60 Furthermore, the sweat test will be performed on siblings, 61 and comparison data can be invaluable. Even though there may appear to be less need of a sweat test in the presence of meconium ileus because meconium ileus provides obvious evidence of a physiological defect, a sweat test revealing elevated chloride should still be the criterion to confirm the diagnosis.…”

Section: The Many Potential Meanings Of a Positive Cf Nbs Testmentioning

confidence: 99%

“…However, because the polyT tract is highly significant in individuals with R117H, it should be added to the diagnostic evaluation to better identify, early on, infants with CF vs those who should be categorized as CRMS/CF screen positive, inconclusive diagnosis (CFSPID), with a risk of converting to a CF diagnosis 74 (Appendix, case study 1; available at www.jpeds.com). There are also uncommon instances of 2 CF-causing mutations occurring in cis 60,75 ; in this scenario, the sweat test would be normal and additional genetic analysis including parental testing could explain the result and prevent medicalization of this healthy infant.…”

Section: Confirming Cf Diagnosis After Positive Newborn Irt/dna Screementioning

confidence: 99%

“…It may be delayed because of illness, prematurity, or, rarely, other circumstances (eg, geographic or weather-related) but should not otherwise be delayed. A CF diagnosis is considered confirmed only if: (1) sweat chloride is ≥60 mmol/L; (2) CF-causing CFTR mutations are identified and the sweat chloride value is ≥30 mmol/ L; (3) 2 variable or uncharacterized CFTR mutations are identified and physiological testing such as NPD or ICM reveal CFTR dysfunction, and the sweat chloride value is ≥30 mmol/L; (4) 2 CF-causing CFTR mutations are identified from a blood specimen obtained directly from the affected infant during follow-up-a genotype report from the NBS program is not sufficient because of the risk of errors (parental testing may be required in some circumstances to verify that 2 mutations are in trans, 60…”

Section: Guidelines For Date Of Confirmation Of Cf Diagnosis Subsequementioning

confidence: 99%

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Diagnosis of Cystic Fibrosis in Screened Populations

Farrell¹,

White

Howenstine

et al. 2017

The Journal of Pediatrics

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It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis.

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“…Using EGA, a higher number of variants is expected to require confirmation because of an increased detection and the possible technical limitation of NGS. Familial segregation analysis is also essential to confirm compound heterozygosity and to avoid false-positive results due to numerous complex alleles reported in the CFTR gene [46,53,54]. Parents' blood sampling for DNA analysis should therefore be carried out optimally during the first visit so that medical care is not delayed.…”

Section: Sequencing and Bioinformatics Limitations For Variant Detectionmentioning

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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A false positive newborn screening result due to a complex allele carrying two frequent CF-causing variants

Cited by 15 publications

References 20 publications

Processing Newborn Bloodspot Screening Results for CF

Processing Newborn Bloodspot Screening Results for CF

Diagnosis of Cystic Fibrosis in Screened Populations

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

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