Expanded Carrier Screening Detects Early Actionable Metabolic Conditions
Prenatal Genetics
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Introduction:
Reproductive carrier screening (CS) panels include up to several hundred genes, many of which are associated with metabolic conditions. Risk assessment for metabolic conditions that have potential for presymptomatic medical or dietary intervention (early actionable metabolic conditions [EAMC]) could have clinical utility beyond newborn screening (NBS) alone. However, it is unclear how often these conditions are identified before birth through CS, and the potential benefit of early risk assessment for these conditions has not been quantified. Our objective was to compare carrier frequencies of EAMCs across two different expanded CS panels and estimate the number of potentially affected pregnancies.
Methods:
This retrospective study analyzed CS results from female patients who had testing at a commercial laboratory with either the ACMG recommended 113-gene Tier 3 CS panel or a 274/275-gene CS panel (1/2020 - 8/2024). Metabolic conditions were identified per the International Classification of Inherited Metabolic Disorders and by expert review. Those with autosomal recessive (AR) or X-linked (XL) inheritance and with ≥90% penetrance were further assessed for early actionability.
EAMCs were defined as conditions included on the Recommended Uniform Screening Panel (RUSP) with established or experimental presymptomatic medical or dietary interventions available within the first week of life (before NBS results) or conditions not on the RUSP that have potential for interventions before 5 years of age. Two genes were excluded from the analysis: CYP21A2 due to limited data available on phasing for patients with multiple variants, and BTD due to a preponderance of the D444H allele which does not cause disease when homozygous.
Gene-specific carrier detection rates were calculated for each EAMC. The number of at-risk pregnancies was calculated by squaring the gene-specific carrier frequencies for AR conditions to simulate random within-population pairing and multiplying the sum of the AR and XL gene-specific at-risk estimates with the total study population. The estimated number of affected pregnancies was then derived by multiplying the number of at-risk pregnancies by 0.25. The estimated number of affected pregnancies was also extrapolated across the annual US births (N = 3,591,328).
Results:
Of 45,721 cases, 34,349 were screened using the 274-gene CS panel and 11,372 using the 113-gene panel. We identified 108 EAMC genes across both panels (107 of 274, 34 of 113).
The three EAMCs with the highest carrier frequencies were phenylketonuria (PAH, 2.4%), glycogen storage disease II (GAA, 2.1%), and Wilson disease (ATP7B, 1.4%) which may present as early as 3 years of age and benefits from presymptomatic therapy. The overall carrier frequency for any EAMC was 27.7% for the 274-gene panel and 15.1% for the 113-gene panel.
Assuming random pairing, the at-risk pregnancy rate for all EAMCs if tested with the 274-gene panel was 0.32%, and the affected-pregnancy rate was 0.08% (1 in 1250). For the 113-gene panel, the at-risk pregnancy rate was 0.24%, and the affected-pregnancy rate was 0.06% (1 in 1667).
Screening the entire study population with either the 274-gene or ACMG panel would detect an estimated 37 or 27 pregnancies affected with EAMCs, respectively. Similarly, we estimate that screening the US birthing population with either the 274-gene or ACMG panel would detect 2865 or 2050 EAMCs per year, respectively.
Conclusion:
Our study demonstrates that expanded CS can identify EAMCs and potentially avert morbidity or mortality by prompting presymptomatic diagnosis and intervention. Compared with ACMG-recommended Tier 3 testing, screening with the larger 274-gene panel would result in a 37% increase in prenatally detected EAMCs that are either not included on the RUSP Core panel or could benefit from treatment before NBS results are available.
Reproductive carrier screening (CS) panels include up to several hundred genes, many of which are associated with metabolic conditions. Risk assessment for metabolic conditions that have potential for presymptomatic medical or dietary intervention (early actionable metabolic conditions [EAMC]) could have clinical utility beyond newborn screening (NBS) alone. However, it is unclear how often these conditions are identified before birth through CS, and the potential benefit of early risk assessment for these conditions has not been quantified. Our objective was to compare carrier frequencies of EAMCs across two different expanded CS panels and estimate the number of potentially affected pregnancies.
Methods:
This retrospective study analyzed CS results from female patients who had testing at a commercial laboratory with either the ACMG recommended 113-gene Tier 3 CS panel or a 274/275-gene CS panel (1/2020 - 8/2024). Metabolic conditions were identified per the International Classification of Inherited Metabolic Disorders and by expert review. Those with autosomal recessive (AR) or X-linked (XL) inheritance and with ≥90% penetrance were further assessed for early actionability.
EAMCs were defined as conditions included on the Recommended Uniform Screening Panel (RUSP) with established or experimental presymptomatic medical or dietary interventions available within the first week of life (before NBS results) or conditions not on the RUSP that have potential for interventions before 5 years of age. Two genes were excluded from the analysis: CYP21A2 due to limited data available on phasing for patients with multiple variants, and BTD due to a preponderance of the D444H allele which does not cause disease when homozygous.
Gene-specific carrier detection rates were calculated for each EAMC. The number of at-risk pregnancies was calculated by squaring the gene-specific carrier frequencies for AR conditions to simulate random within-population pairing and multiplying the sum of the AR and XL gene-specific at-risk estimates with the total study population. The estimated number of affected pregnancies was then derived by multiplying the number of at-risk pregnancies by 0.25. The estimated number of affected pregnancies was also extrapolated across the annual US births (N = 3,591,328).
Results:
Of 45,721 cases, 34,349 were screened using the 274-gene CS panel and 11,372 using the 113-gene panel. We identified 108 EAMC genes across both panels (107 of 274, 34 of 113).
The three EAMCs with the highest carrier frequencies were phenylketonuria (PAH, 2.4%), glycogen storage disease II (GAA, 2.1%), and Wilson disease (ATP7B, 1.4%) which may present as early as 3 years of age and benefits from presymptomatic therapy. The overall carrier frequency for any EAMC was 27.7% for the 274-gene panel and 15.1% for the 113-gene panel.
Assuming random pairing, the at-risk pregnancy rate for all EAMCs if tested with the 274-gene panel was 0.32%, and the affected-pregnancy rate was 0.08% (1 in 1250). For the 113-gene panel, the at-risk pregnancy rate was 0.24%, and the affected-pregnancy rate was 0.06% (1 in 1667).
Screening the entire study population with either the 274-gene or ACMG panel would detect an estimated 37 or 27 pregnancies affected with EAMCs, respectively. Similarly, we estimate that screening the US birthing population with either the 274-gene or ACMG panel would detect 2865 or 2050 EAMCs per year, respectively.
Conclusion:
Our study demonstrates that expanded CS can identify EAMCs and potentially avert morbidity or mortality by prompting presymptomatic diagnosis and intervention. Compared with ACMG-recommended Tier 3 testing, screening with the larger 274-gene panel would result in a 37% increase in prenatally detected EAMCs that are either not included on the RUSP Core panel or could benefit from treatment before NBS results are available.