Applying whole-genome sequencing in relation to phenotype and outcomes in siblings with cystic fibrosis

Abstract

Variations in disease onset and/or severity have often been observed in siblings with cystic fibrosis (CF), despite the same CFTR genotype and environment. We postulated that genomic variation (modifier and/or pharmacogenomic variants) might explain these clinical discordances. From a cohort of patients included in the Wisconsin randomized clinical trial (RCT) of newborn screening (NBS) for CF, we identified two brothers who showed discordant lung disease courses as children, with one milder and the other more severe than average, and a third, eldest brother, who also has severe lung disease. Leukocytes were harvested as the source of DNA, and whole-genome sequencing (WGS) was performed. Variants were identified and analyzed using in-house-developed informatics tools. Lung disease onset and severity were quantitatively different between brothers during childhood. The youngest, less severely affected brother is homozygous for HFE p.H63D. He also has a very rare PLG p.D238N variant that may influence host-pathogen interaction during chronic lung infection. Other variants of interest were found differentially between the siblings. Pharmacogenomics findings were consistent with the middle, most severely affected brother having poor outcomes to common CF treatments. We conclude that genomic variation between siblings with CF is expected. Variable lung disease severity may be associated with differences acting as genetic modifiers and/or pharmacogenomic factors, but large cohort studies are needed to assess this hypothesis.

Clinical and genetic characteristics of children with cystic fibrosis in Henan China: A single‐center retrospective analysis

“…Case 5‐1/5‐2 and Case 6‐1/6‐2 are siblings with the same family background, but their clinical symptoms vary in severity. Wilk MA et al found that even patients with homozygous F508del mutations or siblings with identical CFTR genotype and family environments can have different lung disease severity 19 . The possible involvement of regulating genes is considered.…”

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

“…Exploring nutrigenomic and pharmacogenomic variants that are CF-relevant and can be readily identified with WGS appears to be fruitful according to our preliminary data [58,59]. A recently published study of siblings with different lung disease manifestations but an identical CFTR genotype predicting severe disease (p.Phe508del/CFTRdele2,3) generated WGS data that were informative [58].…”

“…With universal NBS for CF identifying presymptomatic patients, better opportunities have emerged for closing these gaps. Thus, Wisconsin recently launched a project entitled "Assessing the Added Value of Whole Genome Sequencing in Cystic Fibrosis Newborn Screening" to address the hypothesis that identifying non-CFTR genetic variants in individual patients could enlighten therapeutic decision-making [58]. Particular attention is being given to potential genetic modifiers of lung disease and nutrigenomic/pharmacogenomic variants related to common medications.…”

Defining and identifying early‐onset lung disease in cystic fibrosis with cumulative clinical characteristics

“…There is great heterogeneity in the severity of CF, particularly in both the onset and the progression of lung disease 14–18 . Even among patients homozygous for the F508del variant or siblings with the same CFTR genotype and home environment, the severity of lung disease is variable 19 . This heterogeneity appears during the first few years of life 4,11 but is challenging to recognize or predict definitively with current care practices.…”

“…[14][15][16][17][18] Even among patients homozygous for the F508del variant or siblings with the same CFTR genotype and home environment, the severity of lung disease is variable. 19 This heterogeneity appears during the first few years of life 4,11 but is challenging to recognize or predict definitively with current care practices. Although high sensitivity assessment methods like chest CT and lung clearance index (LCI) by the multiple breath washout technique are promising, 20,21 they apply best to research studies rather than routine practice.…”