(364) Detection of Disease-Causing CFTR Variants In State Newborn Screening Programs

Background: Early diagnosis of CF by newborn screening (NBS) is associated with improved nutritional outcomes, pulmonary outcomes, and survival. Newborn screening algorithms vary between state NBS programs in the U.S., but includes measurement of IRT and, when elevated, a CFTR variant panel. In most states, detection of at least 1 variant is required for a test to be reported as out-of-range. Although race and ethnicity are social constructs, CFTR variant distribution varies between racial and ethnic groups depending on ancestry admixture. Minoritized racial and ethnic groups more often have rare or de novo variants not represented on panels.

Methods: Our objectives were 1) to identify differences in detection rate by census-defined racial and ethnic group for common CFTR variant panels, 2) Identify each U.S. state detection rate for frequently used CFTR variant panels based on state population, and 3) describe the rate of false negative NBS tests and delayed diagnoses reported to the CF Foundation Patient Registry by race and ethnicity.

This is a cross-sectional analysis of the detection rate of at least 1 or 2 CFTR variants for seven CFTR variant panels by race and ethnicity in all genotyped people with CF or CRMS/CFTR-related disorder in CFFPR in 2020. The variant panels were ACOG (23 variants), Agena (77 variants), Luminex 39 (39 variants), Luminex60 (60 variants), illumina139 (139 variants), WI-expanded (285 variants), and MCVVs (329 variants). We then estimated the case detection rate of CFTR variant panels for U.S. states by applying the detection rate for each racial and ethnic group to the 2020 U.S. Census data. Lastly, we compared the race and ethnicity of people with CF who had a delayed diagnosis or false-negative newborn screen.

Results: There was a higher detection rate of CFTR variants for all races and ethnicities using higher variant panels compared to fewer variants. For all panels, detection of 1 or 2 CFTR variants was highest in non-Hispanic White people with CF, while detection of 1 or 2 CFTR variants was lowest in Black/African American, Asian, and Hispanic people with CF (Table 1). Compared to CF, detection of CFTR variants was lower in people with CRMS/CFTR-related disorder for all variant panels. There was low case detection of 2 CFTR variants for all races and ethnicities except for non-Hispanic White people with CRMS/CFTR-related disorders. Detection of 1 CFTR variant was lowest in Black/African American and Asian people with CRMS/CFTR-related disorders.

States with increased racial and ethnic diversity had lower detection rates for each variant panel. Detection varied between states for all variant panels. In people with CF, detection of 1 CFTR variant with ACOG panel ranged between 78.0% in Hawaii to 93.5% in Maine while MCVVs panel ranged from 89.0% in Hawaii to 96.3% in Maine.

From 2011-2020, 276 (3.8%) people were diagnosed after a false negative NBS, including 6.5% Black/African American, 15.5% Hispanic, and 5.0% mixed-race people, which is an over-representation compared to the CF population. Also 378 (11.8%) people had a delayed diagnosis, including 6.5% Black/African American, 23.1% Hispanic, and 5.7% mixed race people. Non-Hispanic White people were under-represented in both false negative newborn screening (70.1%) and delayed diagnosis (62.5%).

Conclusions: CFTR variant panels have lower detection rates in minoritized racial and ethnic groups leading to false negative screening, delayed diagnosis, and likely health disparities.

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