The Clinical Impact of CLIR Tools toward Rapid Resolution of Post-Newborn Screening Confirmatory Testing for X-Linked
Hao Tang1, Jamie Matteson1, Piero Rinaldo2
1Genetic Disease Screening Program, California Department of Public Health, Richmond, CA 94804, USA; jamie.matteson@cdph.ca.gov (J.M.); stanley.sciortino@cdph.ca.gov (S.S.).
Insights
Newborn screening for X-linked adrenoleukodystrophy (ALD) often identifies variants of uncertain significance (VUS). A post-analytical tool (CLIR) helps confirm true ALD cases, reducing potential false positives by up to 65%.
Area of Science:
- Genetics
- Biochemistry
- Newborn Screening
Background:
- X-linked adrenoleukodystrophy (ALD) newborn screening in California frequently identifies ATP binding cassette subfamily D member 1 (ABCD1) gene variants of uncertain significance (VUS).
- Distinguishing true ALD cases from VUS is crucial for accurate diagnosis and management.
Purpose of the Study:
- To retrospectively assess the utility of a web-based post-analytical tool, Collaborative Laboratory Integrated Reports (CLIR), in determining the likelihood of true positive ALD cases among infants with ABCD1 VUS.
- To evaluate the tool's consistency with established variant classifications and current diagnoses.
Main Methods:
- Confirmatory plasma very long-chain fatty-acids (VLCFA) profiles from ALD screen-positive infant boys were analyzed using the CLIR ALD tool.
- ABCD1 variant classifications (pathogenic, likely pathogenic, VUS, no variant) were compared with CLIR tool interpretations (non-informative, possibly ALD, likely ALD, very likely ALD) and case diagnoses.
Main Results:
- CLIR tool positive interpretations aligned with 100% of pathogenic and likely pathogenic ABCD1 variants under conservative guidelines.
- The CLIR tool identified 19 diagnosed ALD cases with VUS as potential false positives, a 40% reduction.
- This false positive reduction could reach 65% with a more aggressive threshold.
Conclusions:
- The CLIR tool effectively aids in confirming ALD diagnoses and reducing false positives, particularly among cases with ABCD1 VUS.
- Implementing this tool can significantly alleviate the follow-up burden on patients, families, and healthcare systems.
- This approach enhances the accuracy and efficiency of newborn screening programs for ALD.
Abstract:
Since the start of X-linked adrenoleukodystrophy (ALD) newborn screening in California, more than half of the diagnosed cases were found to have an ATP binding cassette subfamily D member 1 (ABCD1) gene variant of uncertain significance (VUS). To determine retrospectively the likelihood that these were true positive cases, we used a web-based post-analytical tool in Collaborative Laboratory Integrated Reports (CLIR). Confirmatory plasma very long-chain fatty-acids (VLCFA) profiles for ALD screen positive infant boys were run through the CLIR ALD tool. We compared the distribution by ABCD1 variant classification (pathogenic, likely pathogenic, VUS, and no variant) with the CLIR tool score interpretation (non-informative, possibly ALD, likely ALD, and very likely ALD) and the current case diagnosis. The study showed that CLIR tool positive interpretations were consistent with 100% of the pathogenic and likely pathogenic variants on the ABCD1 gene if a more conservative guideline was used. The tool interpretations were also consistent with screened cases that were determined to not have disease (our no-disorder group). The CLIR tool identified 19 diagnosed ALD cases with VUS to be potential false positives, representing a 40% reduction among all diagnosed ALD cases with VUS. The reduction could be extended to 65% if a more aggressive threshold was used. Identifying such preventable false positives could alleviate the follow-up burden for patients, their families, and California Special Care Centers.
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