Genotype-phenotype correlations of cystic fibrosis in siblings compound heterozygotes for rare variant combinations: Review of literature and case report

Tkemaladze, Tinatin; Kvaratskhelia, Eka; Ghughunishvili, M; Lentze, Michael J.; Abzianidze, Elene; Skrahina, Volha; Rolfs, Arndt

doi:10.1016/j.rmcr.2022.101750

Cited by 2 publications

(4 citation statements)

References 19 publications

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“…13,14 In this article, we present the retrospective analysis of three patients with 1677delTA/L997F genotype (Table 1). This work is a continuation of the case described by Tkemaladze et al, 15 in which the researchers presented a familial case of CF with a rare combination of alleles.…”

Section: Introductionsupporting

confidence: 56%

“…This study is a continuation of our previous study where we described the familial case of CF with rare genotype. 15 Family members included two children with classic CF (12-year-old boy and 9-year-old girl with the same I1234V/1677delTA genotype), one child with atypical CF (7-year-old girl with I1234V/L997F alleles) and their apparently healthy mother (43-year-old female with 1677delTA/L997F). In this family, the mother and her daughter were compound heterozygotes and shared L997F allele in combinations with different pathogenic alleles—1677delTA for the mother and I1234V for the child.…”

Section: Discussionmentioning

confidence: 99%

“…This case demonstrates that L997F allele causes phenotypic variability when combined with other pathogenic alleles. 15 It should be noted that L99F variant is considered a non-CF causing variant according to CFTR2 6 and reported as a CFTR-RD-causing 16 or as a variant of variable clinical consequence. 17 The clinical phenotype of the 1677delTA/L99F genotype can therefore be unpredictable.…”

Section: Discussionmentioning

confidence: 99%

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Additional evidence on the phenotype produced by combination of CFTR 1677delTA alleles and their relevance in causing CFTR-related disease

Tkemaladze,

Kvaratskhelia,

Ghughunishvili

et al. 2023

SAGE Open Medical Case Reports

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Cystic fibrosis is the most common, life-threatening, autosomal recessive disease in the Caucasian population. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene, which encodes a chloride ion channel expressed on the surface of epithelial cells. There are more than 2000 variants of the cystic fibrosis transmembrane conductance regulator gene reported worldwide. Some of these variants cause classic cystic fibrosis, while others are labeled as variants of unknown significance or variants of varying clinical consequences alleles and associated with atypical disease or cystic fibrosis transmembrane conductance regulator-related disorders. Although these alleles do not directly cause cystic fibrosis, they may predispose compound heterozygous patients to certain clinical phenotypes. Specifically, 1677delTA has been reported as a pathogenic allele in homozygous state or in combination with other cystic fibrosis-causing alleles. However, the L997F allele is considered to be benign or causative of non-classic cystic fibrosis or cystic fibrosis transmembrane conductance regulator-related disorders in combination with other pathogenic alleles. In this case series, we describe three cases with 1677delTA and L997F genotype, and speculate that a co-concurrence of these two alleles in trans does not cause classic cystic fibrosis symptoms; however, because the late-onset of cystic fibrosis is possible in the presence of rare alleles, such as L997F, longer follow-up of these patients and identification of a greater number of adults with 1677delTA/L997F genotype are necessary to make final conclusion about the nature of this genotype.

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Section: Introductionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Additional evidence on the phenotype produced by combination of CFTR 1677delTA alleles and their relevance in causing CFTR-related disease

Tkemaladze,

Kvaratskhelia,

Ghughunishvili

et al. 2023

SAGE Open Medical Case Reports

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“…The process of CFTR phasing is critical in differentiating a likely heterozygote, with all variants inherited in cis from the same parent, from an infant with variants on both copies of CFTR who needs ongoing monitoring for CFSPID/CRMS. A consequence of the phasing process might be the identification of parents who have either two variants or complex alleles themselves and who are asymptomatic or mildly symptomatic [ 58 ]. These results require additional time for explanation to the parents.…”

Section: Clarifying the Diagnostic Status: Cftr Phasingmentioning

confidence: 99%

Diagnostic and Communication Challenges in Cystic Fibrosis Newborn Screening

DeCelie-Germana

Bonitz

Langfelder‐Schwind

et al. 2023

Life

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As of December 2009, cystic fibrosis (CF) newborn screening (NBS) is performed in all 50 US states and the District of Columbia. Widespread implementation of CF newborn screening (CFNBS) in the US and internationally has brought about new and varied challenges. Immunoreactive trypsinogen (IRT) remains the first, albeit imperfect, biomarker used universally in the screening process. Advances in genetic testing have provided an opportunity for newborn screening programs to add CFTR sequencing tiers to their algorithms. This in turn will enable earlier identification of babies with CF and improve longer-term outcomes through prompt treatment and intervention. CFTR sequencing has led to the ability to identify infants with CF from diverse ethnic and racial backgrounds more equitably while also identifying an increasing proportion of infants with inconclusive diagnoses. Using the evolution of the New York State CF newborn screening program as a guide, this review outlines the basic steps in a universal CF newborn screening program, considers how to reduce bias, highlights challenges, offers guidance to address these challenges and provides recommendations for future consideration.

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Genotype-phenotype correlations of cystic fibrosis in siblings compound heterozygotes for rare variant combinations: Review of literature and case report

Cited by 2 publications

References 19 publications

Additional evidence on the phenotype produced by combination of CFTR 1677delTA alleles and their relevance in causing CFTR-related disease

Additional evidence on the phenotype produced by combination of CFTR 1677delTA alleles and their relevance in causing CFTR-related disease

Diagnostic and Communication Challenges in Cystic Fibrosis Newborn Screening

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