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.

Keywords: bronchiectasis; chronic lung disease; diabetes mellitus; elevated sweat chloride; exocrine pancreatic insufficiency; meconium ileus; multiple bilateral pneumothoraces; recurrent Aspergillus infections; recurrent respiratory infections.

Figure 1.

Pulmonary function test results in the three brothers (i.e., percent predicted FEV1 [ppFEV1] values as related to age). The data obtained on three brothers are shown as A (eldest), B (middle), and C (youngest) and demonstrated that the youngest had better pulmonary function than his brothers. After 20 yr, the eldest brother deteriorated and reached 20% at 28 yr of age.

Figure 2.

Wisconsin chest X-ray scores (Koscik et al. 2000) in the three brothers as compared to published data (Farrell et al. 2003) from the Wisconsin randomized clinical trial (RCT) of the newborn screening (NBS) cohort in which a thoracic radiologist and pediatric pulmonologist rated chest radiographs independently, with their scores being averaged. The data obtained on three brothers are shown as A (eldest), B (middle), and C (youngest) and demonstrated that the youngest had lower and therefore milder lung disease than his brothers throughout childhood. In the case of the eldest brother labeled A, the scores assigned by the same pediatric pulmonologist were adjusted to conform with the averaging method. The gray shaded area labeled D represents the mean ± 95% confidence interval for the entire RCT cohort. (CXR) Chest X-ray.