Inequities in Eligibility for Cystic Fibrosis Modulator Therapy Based on Pathogenic/Likely Pathogenic CFTR Gene Variants Identified Through Carrier Screening
Clinical Genetics and Therapeutics
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Primary Categories:
- Health Care Inequities and health disparities
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Secondary Categories:
- Health Care Inequities and health disparities
Introduction:
While past treatments for cystic fibrosis (CF) focused on symptom management, the development of targeted highly effective modulator therapy (HEMT) has dramatically improved outcomes for CF patients. Patients with CF are only eligible for HEMT if they have at least one CFTR variant that meets eligibility criteria. Modulator therapy acts on existing CFTR proteins and thus requires some protein production. Of the over 2,000 CF-causing gene variants, around 10% are ineligible for HEMT, some because they result in no protein production and others because HEMT has not been validated for these gene variants despite being effective in theory. Black and Hispanic individuals are overrepresented among patients with CF diagnoses who are ineligible for HEMT. However, less is known about the distribution of modulator-eligible and ineligible CFTR variants among carriers. Since carrier screening (CS) is not reliant on symptoms or positive newborn screening, it provides a different view of variant frequencies and distribution. Our objective was to evaluate modulator-eligible and ineligible CFTR variants among patients of different racial and ethnic groups identified as carriers through reproductive CS.
Methods:
Samples received for CS for CFTR in patients older than 18 years at a single commercial laboratory between 01/2020-09/2024 were included. Samples with missing patient race and ethnicity were excluded. Carrier screening was performed through hybrid capture, followed by next-generation sequencing (NGS) with paired-end reads. The entire CFTR gene sequence, including exons, +/-20bp exon-intron boundaries, and selected intronic CFTR variants, were analyzed. CFTR variants identified in carrier patients were compared to the CF Foundation’s list of modulator-eligible variants to generate overall modulator eligibility and ineligibility by reported race and ethnicity. Comparisons between racial and ethnic groups were performed using Dunnett’s test based on a logistic regression.
Results:
Of the 228,868 patients assessed, 34% were White, 11% Hispanic, 8.2% Black, 6.3% multiracial, 5.3% East Asian, 2.1% Ashkenazi Jewish, 2.0% Southeast Asian, and 31% other. Median patient age was 34 years. Most were female (62%); among them, 34% were pregnant. A total of 9,706 pathogenic/likely pathogenic (P/LP) variants in CFTR were identified (carrier frequency: 1 in 24), including 495 distinct variants. Of P/LP variants, 2,129 (22%) were ineligible for modulator therapy. Of the P/LP CFTR variants from Black patients (n=447), 34% of variants were ineligible for therapy. For variants from Hispanic patients (n=789), 29% were ineligible. From East Asian patients (n=147), 29% were ineligible. From Southeast Asian patients (n=186), 22% were ineligible. From multiracial patients (n=583), 22% were ineligible. From other patients (n=2,927), 22% were ineligible. From White patients (n=4,369), 19% were ineligible. From Ashkenazi Jewish patients (n=258), 17% were ineligible. Compared to White individuals, Black (p<0.001) and Hispanic individuals (p<0.001) were significantly more likely to have a P/LP variant ineligible for HEMT. Of the 10 most frequent modulator ineligible variants, 60% (6/10) could be targeted by HEMT, as they were predicted to result in some CFTR protein production.
Conclusion:
Differences in modulator eligibility across racial and ethnic groups were seen when CFTR variants were examined in a large cohort of patients receiving CS, reflecting broader disparities in CF treatment eligibility. Our results provide valuable information for educating patients at the time of carrier screening regarding treatment availability for children who may be affected by CF. To promote equitable access to advancements in treatment, further research is needed to determine if some currently ineligible variants are responsive to existing modulator treatment.
While past treatments for cystic fibrosis (CF) focused on symptom management, the development of targeted highly effective modulator therapy (HEMT) has dramatically improved outcomes for CF patients. Patients with CF are only eligible for HEMT if they have at least one CFTR variant that meets eligibility criteria. Modulator therapy acts on existing CFTR proteins and thus requires some protein production. Of the over 2,000 CF-causing gene variants, around 10% are ineligible for HEMT, some because they result in no protein production and others because HEMT has not been validated for these gene variants despite being effective in theory. Black and Hispanic individuals are overrepresented among patients with CF diagnoses who are ineligible for HEMT. However, less is known about the distribution of modulator-eligible and ineligible CFTR variants among carriers. Since carrier screening (CS) is not reliant on symptoms or positive newborn screening, it provides a different view of variant frequencies and distribution. Our objective was to evaluate modulator-eligible and ineligible CFTR variants among patients of different racial and ethnic groups identified as carriers through reproductive CS.
Methods:
Samples received for CS for CFTR in patients older than 18 years at a single commercial laboratory between 01/2020-09/2024 were included. Samples with missing patient race and ethnicity were excluded. Carrier screening was performed through hybrid capture, followed by next-generation sequencing (NGS) with paired-end reads. The entire CFTR gene sequence, including exons, +/-20bp exon-intron boundaries, and selected intronic CFTR variants, were analyzed. CFTR variants identified in carrier patients were compared to the CF Foundation’s list of modulator-eligible variants to generate overall modulator eligibility and ineligibility by reported race and ethnicity. Comparisons between racial and ethnic groups were performed using Dunnett’s test based on a logistic regression.
Results:
Of the 228,868 patients assessed, 34% were White, 11% Hispanic, 8.2% Black, 6.3% multiracial, 5.3% East Asian, 2.1% Ashkenazi Jewish, 2.0% Southeast Asian, and 31% other. Median patient age was 34 years. Most were female (62%); among them, 34% were pregnant. A total of 9,706 pathogenic/likely pathogenic (P/LP) variants in CFTR were identified (carrier frequency: 1 in 24), including 495 distinct variants. Of P/LP variants, 2,129 (22%) were ineligible for modulator therapy. Of the P/LP CFTR variants from Black patients (n=447), 34% of variants were ineligible for therapy. For variants from Hispanic patients (n=789), 29% were ineligible. From East Asian patients (n=147), 29% were ineligible. From Southeast Asian patients (n=186), 22% were ineligible. From multiracial patients (n=583), 22% were ineligible. From other patients (n=2,927), 22% were ineligible. From White patients (n=4,369), 19% were ineligible. From Ashkenazi Jewish patients (n=258), 17% were ineligible. Compared to White individuals, Black (p<0.001) and Hispanic individuals (p<0.001) were significantly more likely to have a P/LP variant ineligible for HEMT. Of the 10 most frequent modulator ineligible variants, 60% (6/10) could be targeted by HEMT, as they were predicted to result in some CFTR protein production.
Conclusion:
Differences in modulator eligibility across racial and ethnic groups were seen when CFTR variants were examined in a large cohort of patients receiving CS, reflecting broader disparities in CF treatment eligibility. Our results provide valuable information for educating patients at the time of carrier screening regarding treatment availability for children who may be affected by CF. To promote equitable access to advancements in treatment, further research is needed to determine if some currently ineligible variants are responsive to existing modulator treatment.