Utilizing MyCode and population-based genomics screening to detect genetic variants for cardiovascular disease in women of reproductive age
Prenatal Genetics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
The MyCode community health initiative (MyCode) is a clinical research program that implements population-based genomic screening and reports medically actionable results to biobank participants. Population genomic screening identifies at-risk individuals and affords the opportunity to tailor interventions and refer for treatment including changes to routine prenatal managment. In this study, we sought to determine the rate of pathogenic/likely pathogenic (P/LP) genetic variants in cardiovascular disease (CVD) associated genes in women of reproductive age. In doing so we sought to raise awareness that these results impact reproductive counseling and pregnancy management.
Methods:
This was an IRB-approved cross-sectional study involving biobank data from MyCode at Geisinger, from July 2015-October 2024. MyCode biobank participants consent to broad based research, and research exome sequences generated as part of the biobank are leveraged through the genomic screening and counseling program to return actionable findings. This includes genes conferring CVD related risks on the ACMG secondary findings list. We examined the participant demographics from the 175,500 participants with exome sequence data available to restrict to females of reproductive age (18-45 years). We also restricted the 5,054 participants with positive results (2,249 CVD-related) to those who were reproductive age at the time or results. Participants within this range with a result in a CVD gene were categorized based on their result -- cardiomyopathies, amyloidosis, arrythmias, aortopathies, and hypercholesterolemia. AHA(American Heart Associations)/ACC(American College of Cardiology) guidelines were reviewed for any differences in are management for individuals with variants and pregnant or considering pregnancy.
Results:
Over the study period, data for 40,199 female subjects that met inclusion criteria were identified. Of these, 478 (1.2%) P/LP CVD-associated gene variants were identified and disclosed. These were distributed as follows: [numbers of specific variant (% of total at-risk variants for CVD]: 233 for cardiomyopathies [66 (14%) TTN, 49 (10%) MYBPC3] and an additional 44 (9%) hereditary transthyretin amyloidosis (TTR), 75 for arrythmias [36 (7.5%) KCNQ1], 18 for aortopathies [9 (1.8%) ACTA2], and 108 familial hypercholesterolemia [71(15%) LDLR].
Conclusion:
Pregnant patients with a genetic susceptibility to CV conditions require individualized treatment plans. For example, peripartum cardiomyopathy is a diagnosis of exclusion for which the recommended treatment is stabilization and delivery; however, in a patient with a genetic variant known to be at-risk for cardiomyopathy, management may not necessarily include expedited delivery. Similarly, in patients with P/LP variants for connective tissue disorders that confer CV risk, the risk for aortic dissection is greater and cesarean delivery is recommended at a smaller aortic root diameter cutoff compared to those without genetic susceptibility. Additionally, cholesterol levels increase during pregnancy, especially in patients with familial hypercholesterolemia. In this subset of patients, preconception counseling is critical to avoid certain teratogenic medications in the first trimester. Also, given the accelerated increase in cholesterol levels during pregnancy in this condition, multidisciplinary care and consideration of additional treatments later in pregnancy should be considered. Furthermore, the importance of postpartum follow-up and restarting statin therapy must be stressed. Lastly, genetic counseling and possibly in vitro fertilization play an integral role in helping patients with genetic variants navigate pregnancy. Offspring are not only at a 50% chance risk of being affected, but in many instances, there is also a risk for a separate autosomal recessive disease; therefore, partner expanded carrier screening should be explored (e.g. TTN gene and early-onset myopathy with fatal cardiomyopathy). These are only some of the examples where management is impacted by the presence of a known variant. Further study will allow determination of the prevalence of prior subclinical disease and the most appropriate workup for phenotype negative patients of reproductive age in this gene-first cohort.
The MyCode community health initiative (MyCode) is a clinical research program that implements population-based genomic screening and reports medically actionable results to biobank participants. Population genomic screening identifies at-risk individuals and affords the opportunity to tailor interventions and refer for treatment including changes to routine prenatal managment. In this study, we sought to determine the rate of pathogenic/likely pathogenic (P/LP) genetic variants in cardiovascular disease (CVD) associated genes in women of reproductive age. In doing so we sought to raise awareness that these results impact reproductive counseling and pregnancy management.
Methods:
This was an IRB-approved cross-sectional study involving biobank data from MyCode at Geisinger, from July 2015-October 2024. MyCode biobank participants consent to broad based research, and research exome sequences generated as part of the biobank are leveraged through the genomic screening and counseling program to return actionable findings. This includes genes conferring CVD related risks on the ACMG secondary findings list. We examined the participant demographics from the 175,500 participants with exome sequence data available to restrict to females of reproductive age (18-45 years). We also restricted the 5,054 participants with positive results (2,249 CVD-related) to those who were reproductive age at the time or results. Participants within this range with a result in a CVD gene were categorized based on their result -- cardiomyopathies, amyloidosis, arrythmias, aortopathies, and hypercholesterolemia. AHA(American Heart Associations)/ACC(American College of Cardiology) guidelines were reviewed for any differences in are management for individuals with variants and pregnant or considering pregnancy.
Results:
Over the study period, data for 40,199 female subjects that met inclusion criteria were identified. Of these, 478 (1.2%) P/LP CVD-associated gene variants were identified and disclosed. These were distributed as follows: [numbers of specific variant (% of total at-risk variants for CVD]: 233 for cardiomyopathies [66 (14%) TTN, 49 (10%) MYBPC3] and an additional 44 (9%) hereditary transthyretin amyloidosis (TTR), 75 for arrythmias [36 (7.5%) KCNQ1], 18 for aortopathies [9 (1.8%) ACTA2], and 108 familial hypercholesterolemia [71(15%) LDLR].
Conclusion:
Pregnant patients with a genetic susceptibility to CV conditions require individualized treatment plans. For example, peripartum cardiomyopathy is a diagnosis of exclusion for which the recommended treatment is stabilization and delivery; however, in a patient with a genetic variant known to be at-risk for cardiomyopathy, management may not necessarily include expedited delivery. Similarly, in patients with P/LP variants for connective tissue disorders that confer CV risk, the risk for aortic dissection is greater and cesarean delivery is recommended at a smaller aortic root diameter cutoff compared to those without genetic susceptibility. Additionally, cholesterol levels increase during pregnancy, especially in patients with familial hypercholesterolemia. In this subset of patients, preconception counseling is critical to avoid certain teratogenic medications in the first trimester. Also, given the accelerated increase in cholesterol levels during pregnancy in this condition, multidisciplinary care and consideration of additional treatments later in pregnancy should be considered. Furthermore, the importance of postpartum follow-up and restarting statin therapy must be stressed. Lastly, genetic counseling and possibly in vitro fertilization play an integral role in helping patients with genetic variants navigate pregnancy. Offspring are not only at a 50% chance risk of being affected, but in many instances, there is also a risk for a separate autosomal recessive disease; therefore, partner expanded carrier screening should be explored (e.g. TTN gene and early-onset myopathy with fatal cardiomyopathy). These are only some of the examples where management is impacted by the presence of a known variant. Further study will allow determination of the prevalence of prior subclinical disease and the most appropriate workup for phenotype negative patients of reproductive age in this gene-first cohort.