Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk

Lim, Regine M.; Silver, Ari J.; Silver, Maxwell; Borroto, Carlos; Spurrier, Brett; Petrossian, Tanya C.; Larson, Jessica L.; Silver, Lee M.

doi:10.1038/gim.2015.52

Cited by 22 publications

(25 citation statements)

References 29 publications

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“…Although African genomes are known to be highly diverse 36 they also tend to be understudied which is the case with CF, especially since it was assumed that this disease could only affect those of European or Caucasian descent 37 .…”

Section: Issues Surrounding Diagnosing Cf In the Diasporamentioning

confidence: 99%

“…This may increase their chances of being misdiagnosed especially in areas where there are more rampant phenocopic illnesses such as malnutrition, viral or parasitic infection or tuberculosis 11,38 . Second, there is not enough information available about the mutations present in these sub-populations for the design of suitable genetic tests 12,37 . This also increases the probability that these patients may be misdiagnosed particularly if they don't present with the classic triad of CF symptoms or if they have milder forms of the disease.…”

Section: The Way Forwardmentioning

confidence: 99%

“…Based on the available data, CF patients in the African Diaspora are at a distinct disadvantage when compared to their European counterparts 11,37 . Global data suggests that the number of CF causing mutations in patients of European descent may be approaching a plateau.…”

Section: The Way Forwardmentioning

confidence: 99%

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Cystic Fibrosis in the African Diaspora

Stewart

Pepper

2017

Annals ATS

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Identifying mutations that cause cystic fibrosis (CF) is important for making an early, unambiguous diagnosis, which in turn is linked to better health and a greater life expectancy. In patients of African descent, a molecular diagnosis is often confounded by the fact that the majority of investigations undertaken to identify causative mutations have been conducted on European populations, and CF-causing mutations tend to be population specific. We undertook a survey of published data with the aim of identifying causative CF mutations in patients of African descent in the Americas. We found that 1,584 chromosomes had been tested in only six countries of which 876 alleles (55.3%) still remained unidentified. There were 59 mutations identified -41 of which have been shown to cause CF, 17 have no associated functional studies and one (R117H) is of varying clinical consequence. The most common mutations identified in the Diaspora were ΔF508 (29.4%; identified in America, Colombia, Brazil and Venezuela), 3120+1G>A (8.4%; identified in Brazil, America and Colombia), G85E (3.8% identified in Brazil), 1811+1.6kbA>G (3.7% identified in Colombia), and 1342-1G>C (3.1% identified in America). The majority of the mutations identified (81.4%) have been described in just one country. Our findings indicate that there is a need to fully characterise the spectrum of CF mutations in the Diaspora in order to improve diagnostic accuracy for these patients and facilitate treatment.2

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Section: Issues Surrounding Diagnosing Cf In the Diasporamentioning

confidence: 99%

Section: The Way Forwardmentioning

confidence: 99%

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Cystic Fibrosis in the African Diaspora

Stewart

Pepper

2017

Annals ATS

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“…Should we continue proposing the 23 pan-ethnic mutation panel suggested by ACOG/ACMG/NIH [47], should we test for all pathogenic mutations present in the screened population that appear with a frequency even lower to the "gold standard" of 0.1% or should we screen the whole gene and report only pathogenic / likely pathogenic variants even if they are novel following the "Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology" [60]. This question has no easy answer and has raised a lot of debate [61,62] and we believe that the best approach should be custom-made for each distinct population.…”

Section: Carrier Screening: What Lies Ahead?mentioning

confidence: 99%

Carrier Screening for Cystic Fibrosis: Past, Present and Future

Poulou¹,

Tzetis²

2017

obm genet

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Cystic Fibrosis (CF) is one of the commonest autosomal recessive genetic diseases that show a high carrier frequency amongst Caucasian populations. Although there has been tremendous progress in the available therapies, compared to the past, the disease is still associated with significant morbidity and mortality. Because of the severe clinical manifestations and the shortened life expectancy of patients, population based carrier screening, to identify heterozygous carrier couples at risk of having affected children, has been recommended. We review the history of population based carrier screening for CF, focusing on the screening guidelines, the current requirements and the difficulties of implementation, considering especially the heterogeneity of CF-causing mutations.

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“…This represents most alleles seen in patients with CF, but the large number of untested remaining variants may contain variants more common in non-Europeans. 8 Second, certain annotated mutations may cause CF in some individuals or may result in no phenotype. In the study by Kharazzi et al, 3 both occurrences resulted in newborns with a CFTRrelated metabolic syndrome (CRMS) diagnosis.…”

Section: Recent Advances In Cftr Geneticsmentioning

confidence: 99%