The Genetics of CFTR: Genotype - Phenotype Relationship, Diagnostic Challenge and Therapeutic Implications

Lucarelli, Marco; Pierandrei, Silvia; Bruno, Sabina Maria; Strom, Roberto

doi:10.5772/30281

Cited by 8 publications

(7 citation statements)

References 195 publications

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“…The ability of complex alleles to give rise to more severe forms of CF and higher sweat test values was highlighted for three of these complex alleles. These data, together with those in the literature (see Lucarelli et al [1]) for a review) indicate that complex alleles may account for a greater degree of variability than is usually acknowledged. To be meaningful, mutational search protocols should be designed to search for complex alleles, at least in cases in which the clinical presentation varies even when the genotype is apparently identical.…”

Section: Discussionmentioning

confidence: 81%

“…It is reasonable to assume that this transition is more likely to be influenced by intragenic (CFTRdependent) variability. It may originate from the large number of sequence variations and be markedly enhanced by their combination in trans and in cis as complex alleles (1,28), as well as by a regulatory posttranscriptional and posttranslational impairment that often escapes recognition. The second step may be defined as the transition from the CFTR protein residual function to clinical phenotype (residual functionality → clinical step).…”

Section: R E S E a R C H A R T I C L Ementioning

confidence: 99%

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A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis

Lucarelli

Bruno

Pierandrei

et al. 2015

Mol Med

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Section: Discussionmentioning

confidence: 81%

Section: R E S E a R C H A R T I C L Ementioning

confidence: 99%

A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis

Lucarelli

Bruno

Pierandrei

et al. 2015

Mol Med

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“…CFTR complex alleles are frequently found in patients, usually associating two or more "mild" variants (e.g. involved in CFTR-Related Disorders), and more rarely one CF-causing variant with "non-neutral" or "mild" variations [6]. This work reports the first complex allele on the CFTR gene that associates two frequent CF-causing variations detected by NBS strategy.…”

Section: Discussionmentioning

confidence: 92%

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

Bergougnoux

Boureau-Wirth

Rouzier

et al. 2016

Journal of Cystic Fibrosis

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The detection of two frequent CFTR disease-causing variations in the context of a newborn screening program (NBS) usually leads to the diagnosis of cystic fibrosis (CF) and a relevant genetic counseling in the family. In the present study, CF-causing variants p.Phe508del (F508del) and c.3140-26A>G (3272-26A>G) were identified on a neonate with positive ImmunoReactive Trypsinogen test by the Elucigene™ CF30 kit. The CF diagnosis initially suggested, despite three inconclusive Sweat Chloride Tests (SCT), was finally ruled out after the familial segregation study combined with a negative SCT. Haplotype studies, based on the comparison of 80 p.Phe508del haplotypes, suggested a probable de novo occurrence of c.3140-26A>G on the p.Phe508del ancestral allele in this family. This false positive case emphasizes the importance of SCT in the NBS strategy. Moreover, it raises the need for familial segregation studies in CF and in overall molecular diagnosis strategy of autosomal recessive diseases.

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“…e . environment, treatment approach, patient’s adherence to therapy) originates a complex genotype–phenotype relationship in CF that, in turn, affects diagnosis, prognosis and personalized therapy [2, 3, 9–15].…”

Section: Introductionmentioning

confidence: 99%

Two novel and correlated CF-causing insertions in the (TG)mTn tract of the CFTR gene

Pierandrei

Blaconà

Fabrizzi³

et al. 2019

PLoS ONE

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Two novel and related pathogenic variants of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene were structurally and functionally characterized. These alterations have not been previously described in literature. Two patients with diagnosis of Cystic Fibrosis (CF) based on the presence of one mutated allele, p.Phe508del, pathological sweat test and clinical symptoms were studied. To complete the genotypes of both patients, an extensive genetic and functional analysis of the CFTR gene was performed. Extensive genetic characterization confirmed the presence of p.Phe508del pathogenic variant and revealed, in both patients, the presence of an insertion of part of intron 10 in intron 9 of the CFTR gene, within the (TG)m repeat, with a variable poly-T stretch. The molecular lesions resulted to be very similar in both patients, with only a difference in the number of T in the poly-T stretch. The functional characterization at RNA level revealed a complete anomalous splicing, without exon 10, from the allele with the insertion of both patients. Consequently, the alleles with the insertions are expected not to contribute to the formation of a functional CFTR protein. Molecular and functional features of these alterations are compatible with the definition of novel CF-causing variants of the CFTR gene. This also allowed the completion of the genetic characterization of both patients.

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The Genetics of CFTR: Genotype - Phenotype Relationship, Diagnostic Challenge and Therapeutic Implications

Cited by 8 publications

References 195 publications

A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis

A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis

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

Two novel and correlated CF-causing insertions in the (TG)mTn tract of the CFTR gene

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