Assessment of Inborn Errors of Metabolism genes on the Recommended Uniform Screening Panel using the ClinGen Clinical Validity framework
Ethical Legal Social Issues (ELSI) Public Health and Policy
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Primary Categories:
- Population Genetics
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Secondary Categories:
- Population Genetics
Introduction:
The Recommended Uniform Screening Panel (RUSP) is a list of conditions recommended by the Health Resources and Services Administration (HRSA), for inclusion in state universal newborn screening (NBS) programs. The RUSP is composed of core conditions, and secondary conditions that may be detected when screening for core conditions. Understanding the clinical validity of genes related to conditions on the RUSP is crucial for follow up evaluation of infants identified by newborn screening (NBS). One goal of the Clinical Genome Resource (ClinGen), an NIH-funded initiative, is to evaluate the clinical relevance of genes in disease. ClinGen uses a semi-quantitative framework to assess the strength of evidence supporting gene-disease relationships. The ClinGen Inborn Errors of Metabolism (IEM) Clinical Domain Working Group (CDWG) has assembled Gene Curation Expert Panels (GCEPs), to evaluate gene-disease clinical validity for specific groups of IEMs including, but not limited to, the genes involved in conditions on the RUSP. As a result, the General IEM GCEP was tasked with ensuring that all genes involved in IEMs on the RUSP have undergone gene-disease clinical validity classification. Here, we summarize the ClinGen General IEM GCEP's assessment of gene-disease validity for those genes.
Methods:
The General IEM GCEP reviewed the current list of RUSP conditions and genes involved with those conditions (https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp). We determined which gene-disease relationships have already been assessed for clinical validity by other ClinGen GCEPs, and the clinical validity classification of those gene-disease relationships. The General IEM GCEP then used the ClinGen Gene Disease Clinical Validity framework to assess the gene-disease validity of the remaining genes.
Results:
HRSA categorizes 20 conditions on the core RUSP as metabolic disorders; the General IEM GCEP included an additional 8 disorders considered to be under our purview. In total 33 genes are involved with these 28 conditions. All but one, GALT, had already been curated by other ClinGen GCEPs and all those gene-disease classifications were definitive. The General IEM GCEP evaluated the clinical validity of GALT-classic galactosemia and classified it as definitive. Therefore, the gene-disease relationships for all conditions on the core RUSP, identified as IEM by the General IEM GCEP, were definitive.
On the secondary RUSP, HRSA described 22 conditions as metabolic disorders; the General IEM GCEP included an additional 2 disorders categorized as “other” on the secondary RUSP list. 38 genes were found to be involved with these 24 conditions. Five of these genes had not yet undergone clinical validity classification by a ClinGen GCEP. These gene-disease relationships were evaluated by the ClinGen General IEM GCEP, and 4 of the 5 were definitive. Of all 38 genes associated with conditions on the secondary RUSP, 33 had a definitive gene-disease clinical validity for the associated condition, 3 were classified as moderate, 1 as limited, and 1 is pending curation by another GCEP. Those with moderate and limited classifications will be re-evaluated by ClinGen on a regular basis, following ClinGen policy.
Conclusion:
While all genes involved in IEM conditions on the core RUSP had a definitive clinical validity classification, the General IEM GCEP found that at least 4 genes associated with conditions on the secondary RUSP are not definitively associated with the condition. This is to be expected considering that conditions on the secondary RUSP are not the primary target of NBS. Understanding clinical validity is important in variant classification. As such, clinical validity classifications should be considered during followup of these neonates, taking into account the positive and negative effects of uncertain NBS results.
The Recommended Uniform Screening Panel (RUSP) is a list of conditions recommended by the Health Resources and Services Administration (HRSA), for inclusion in state universal newborn screening (NBS) programs. The RUSP is composed of core conditions, and secondary conditions that may be detected when screening for core conditions. Understanding the clinical validity of genes related to conditions on the RUSP is crucial for follow up evaluation of infants identified by newborn screening (NBS). One goal of the Clinical Genome Resource (ClinGen), an NIH-funded initiative, is to evaluate the clinical relevance of genes in disease. ClinGen uses a semi-quantitative framework to assess the strength of evidence supporting gene-disease relationships. The ClinGen Inborn Errors of Metabolism (IEM) Clinical Domain Working Group (CDWG) has assembled Gene Curation Expert Panels (GCEPs), to evaluate gene-disease clinical validity for specific groups of IEMs including, but not limited to, the genes involved in conditions on the RUSP. As a result, the General IEM GCEP was tasked with ensuring that all genes involved in IEMs on the RUSP have undergone gene-disease clinical validity classification. Here, we summarize the ClinGen General IEM GCEP's assessment of gene-disease validity for those genes.
Methods:
The General IEM GCEP reviewed the current list of RUSP conditions and genes involved with those conditions (https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp). We determined which gene-disease relationships have already been assessed for clinical validity by other ClinGen GCEPs, and the clinical validity classification of those gene-disease relationships. The General IEM GCEP then used the ClinGen Gene Disease Clinical Validity framework to assess the gene-disease validity of the remaining genes.
Results:
HRSA categorizes 20 conditions on the core RUSP as metabolic disorders; the General IEM GCEP included an additional 8 disorders considered to be under our purview. In total 33 genes are involved with these 28 conditions. All but one, GALT, had already been curated by other ClinGen GCEPs and all those gene-disease classifications were definitive. The General IEM GCEP evaluated the clinical validity of GALT-classic galactosemia and classified it as definitive. Therefore, the gene-disease relationships for all conditions on the core RUSP, identified as IEM by the General IEM GCEP, were definitive.
On the secondary RUSP, HRSA described 22 conditions as metabolic disorders; the General IEM GCEP included an additional 2 disorders categorized as “other” on the secondary RUSP list. 38 genes were found to be involved with these 24 conditions. Five of these genes had not yet undergone clinical validity classification by a ClinGen GCEP. These gene-disease relationships were evaluated by the ClinGen General IEM GCEP, and 4 of the 5 were definitive. Of all 38 genes associated with conditions on the secondary RUSP, 33 had a definitive gene-disease clinical validity for the associated condition, 3 were classified as moderate, 1 as limited, and 1 is pending curation by another GCEP. Those with moderate and limited classifications will be re-evaluated by ClinGen on a regular basis, following ClinGen policy.
Conclusion:
While all genes involved in IEM conditions on the core RUSP had a definitive clinical validity classification, the General IEM GCEP found that at least 4 genes associated with conditions on the secondary RUSP are not definitively associated with the condition. This is to be expected considering that conditions on the secondary RUSP are not the primary target of NBS. Understanding clinical validity is important in variant classification. As such, clinical validity classifications should be considered during followup of these neonates, taking into account the positive and negative effects of uncertain NBS results.