Racial inequities and rare CFTR variants: Impact on cystic fibrosis diagnosis and treatment

Abstract

Cystic fibrosis (CF) has been traditionally viewed as a disease that affects White individuals. However, CF occurs among all races, ethnicities, and geographic ancestries. The disorder results from mutations in the CF transmembrane conductance regulator (CFTR). Varying incidence of CF is reported among Black, Indigenous, and People of Color (BIPOC), who typically exhibit worse clinical outcomes. These populations are more likely to carry rare CFTR variants omitted from newborn screening panels, leading to disparities in care such as delayed diagnosis and treatment. In this study, we present a case-in-point describing an individual of Gambian descent identified with CF. Patient genotype includes a premature termination codon (PTC) (c.2353C>T) and previously undescribed single nucleotide deletion (c.1970delG), arguing against effectiveness of currently available CFTR modulator-based interventions. Strategies for overcoming these two variants will likely include combinations of PTC suppressors, nonsense mediated decay inhibitors, and/or alternative approaches (e.g. gene therapy). Investigations such as the present study establish a foundation from which therapeutic treatments may be developed. Importantly, c.2353C>T and c.1970delG were not detected in the patient by traditional CFTR screening panels, which include an implicit racial and ethnic diagnostic bias as these tests are comprised of mutations largely observed in people of European ancestry. We suggest that next-generation sequencing of CFTR should be utilized to confirm or exclude a CF diagnosis, in order to equitably serve BIPOC individuals. Additional epidemiologic data, basic science investigations, and translational work are imperative for improving understanding of disease prevalence and progression, CFTR variant frequency, genotype-phenotype correlation, pharmacologic responsiveness, and personalized medicine approaches for patients with African ancestry and other historically understudied geographic lineages.

Keywords: African; Cystic fibrosis; Cystic fibrosis-related diabetes; Diagnosis; Genetics; Newborn screening.

Fig. 1

Consequences of c.1970delG in CFTR. At CFTR chromosomal position 1970 (c.1970), deletion of the G nucleotide (delG) confers a DNA frameshift together with premature termination of the protein. Regions of CFTR DNA that encode protein (i.e. exons) are annotated as grey boxes and numbered. For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.

Fig. 2

Chest CT at 11.8y identifies pathological respiratory features. Mild bronchiectasis (right lower lobe, red arrows) and mucus plugging (right middle lobe, green arrows) are demonstrated on coronal (A) and axial (B-C) views. For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.

Fig. 3

Microbial and related pulmonary manifestations over time. Pathogenic cultures show varying microbial taxa since birth. Solid black horizontal lines indicate inferred microbial presence. Vertical grey bars denote APEs (six in total), with line thickness representing length of hospitalization. MRSA, methicillin-resistant Staphylococcus aureus; GNB, Gram-negative bacillus. For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.

Fig. 4

HbA1C and OGTT results show persistent dysglycemia beginning at 4.2y. (A) Pre-diabetic ranges are highlighted for HbA1C (5.7–6.5%; red). (B) Impaired glucose tolerance (140–200 mg/dL; green) and fasting glucose (100–126 mg/dL; blue) are indicated. From the time of CFRD diagnosis (age 6.1y) until B. cepacia was first detected (age 13.8y), HbA1c remained within target (<7%). For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.

Fig. 5

Standing radiograph depicts mild scoliosis (age 11.9y). Findings include dextrocurvature of the thoracic spine (19°) (red) and levocurvature of the thoracolumbar spine (21°) (green). Scoliosis was first incidentally noted from chest radiographs conducted for routine pulmonary care at age 9.2y. For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.

Fig. 6

Sinus CT at 11.3y reveals pansinusitis disease most pronounced in the maxillary sinus. (A) Axial view is notable for mucocele causing complete opacification of the right maxillary sinus (red arrow) and mucosal thickening (green arrow). (B) Coronal view demonstrates patchy mucosal thickening throughout the ethmoid sinuses. For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.