Penetrance and Phenotypic Findings of Cardiovascular Variants Identified from Biobank, Secondary, and Unanticipated Findings in an Adult Clinical Cohort
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
As diagnostic genetic tests are more widespread, both secondary and unanticipated findings are being increasingly identified. Similarly, research biobanks are becoming more prevalent, with one goal being to return actionable genetic findings. In December 2023, UCLA Health launched the ATLAS Genetic Screening Program (GSP), which aims to return actionable findings. As a result, clinics will see an increase in the evaluation and management of secondary findings. To provide more accurate counseling on disease risks, an understanding of the penetrance associated with such findings is essential.
Methods:
A retrospective chart review was performed for patients evaluated in the UCLA Health Adult Cardiovascular Genetics clinic who had a likely pathogenic/pathogenic (LP/P) variant identified in a cardiovascular related gene that was considered to be an unanticipated, secondary, or biobank finding. Patients who received a LP/P cardiovascular variant from the UCLA ATLAS GSP were also included. For genes associated with multisystemic disease, only variants with known cardiac involvement were included. Variables collected from the chart review, included clinical evaluations, diagnoses, and family history relevant to the gene. Individuals with cardiac/lab findings and/or an overt family history specific to their gene variant constituted as having a definitive phenotype. Those with mild or non-specific findings associated with the specific gene variant constituted as having a possibly related phenotype.
Results:
A total of 41 individuals with a LP/P variant were reviewed, of which twenty-seven (66%) were females, with mean age at evaluation being 44.5 years (range: 22-67; SD ± 13). Twenty-three (56%) had their variant identified through a research biobank, the most common disease subcategory being cardiomyopathy (15; 37%), followed by multisystemic (13; 32%), arrhythmia (8; 19%), and hypercholesterolemia (5; 12%). Six (15%) had variants with discordant ClinVar classifications (variant of uncertain significance versus LP/P).
Among 23 individuals with cardiomyopathy or arrhythmia gene variants (LMNA, TTN, MYBPC3, TNNT2, KCNQ1, SCN5A), 17 (74%) have completed at least standard phenotyping (echocardiography for cardiomyopathy gene; electrocardiography for arrhythmia gene), in which 10 had definitive phenotypes.
Of the 5 individuals with hypercholesterolemia gene variants (LDLR, APOB), four had existing lipid panels documenting elevated LDL cholesterol (LDL-C) ranging from 120-204mg/dL, with one having a pre-existing risk factor. The last individual was on high-intensity statin treatment, and pre-treated values were unavailable. Only 1 (20%) had significantly elevated LDL-C (>190mg/dL) and was considered to have a definitive phenotype.
Finally, of the 13 individuals with multisystemic gene variants (TTR, GLA, DMD, FBN1, COL3A1), the TTR Val142Ile founder variant was the most common (7; 56%). Four TTR individuals (age range: 44-66) had at least a cardiac MRI and/or amyloidosis scan, in which 1 (25%) was confirmed to have cardiac amyloidosis and signs of neuropathy, while 1 had confirmed neuropathy. Four females (age range: 35-66) had X-linked gene variants (2 DMD, 2 GLA), with both GLA variants being associated with late onset disease. Echocardiography did not show evidence of relevant cardiac disease, although 1 GLA carrier had biochemical abnormalities and a family history of hypertrophic cardiomyopathy. Two individuals with a connective tissue disease gene (FBN1, COL3A1), had normal echocardiography, with the COL3A1 carrier also having normal vascular imaging; however, connective tissue findings were noted.
In total, 20/41 (49%) individuals had a possibly related phenotype related to their cardiovascular variant, while 11 (55%) had definitive phenotype.
Conclusion:
The disease penetrance of cardiovascular gene variants appears to be high, though with notable variability across disease subcategories. Our findings highlight the broad phenotypic spectrum of inherited cardiovascular diseases, and underscore the necessity of comprehensive phenotyping in individuals receiving actionable cardiovascular variants, as approximately half of patients do not have definitive phenotype for their variant.
As diagnostic genetic tests are more widespread, both secondary and unanticipated findings are being increasingly identified. Similarly, research biobanks are becoming more prevalent, with one goal being to return actionable genetic findings. In December 2023, UCLA Health launched the ATLAS Genetic Screening Program (GSP), which aims to return actionable findings. As a result, clinics will see an increase in the evaluation and management of secondary findings. To provide more accurate counseling on disease risks, an understanding of the penetrance associated with such findings is essential.
Methods:
A retrospective chart review was performed for patients evaluated in the UCLA Health Adult Cardiovascular Genetics clinic who had a likely pathogenic/pathogenic (LP/P) variant identified in a cardiovascular related gene that was considered to be an unanticipated, secondary, or biobank finding. Patients who received a LP/P cardiovascular variant from the UCLA ATLAS GSP were also included. For genes associated with multisystemic disease, only variants with known cardiac involvement were included. Variables collected from the chart review, included clinical evaluations, diagnoses, and family history relevant to the gene. Individuals with cardiac/lab findings and/or an overt family history specific to their gene variant constituted as having a definitive phenotype. Those with mild or non-specific findings associated with the specific gene variant constituted as having a possibly related phenotype.
Results:
A total of 41 individuals with a LP/P variant were reviewed, of which twenty-seven (66%) were females, with mean age at evaluation being 44.5 years (range: 22-67; SD ± 13). Twenty-three (56%) had their variant identified through a research biobank, the most common disease subcategory being cardiomyopathy (15; 37%), followed by multisystemic (13; 32%), arrhythmia (8; 19%), and hypercholesterolemia (5; 12%). Six (15%) had variants with discordant ClinVar classifications (variant of uncertain significance versus LP/P).
Among 23 individuals with cardiomyopathy or arrhythmia gene variants (LMNA, TTN, MYBPC3, TNNT2, KCNQ1, SCN5A), 17 (74%) have completed at least standard phenotyping (echocardiography for cardiomyopathy gene; electrocardiography for arrhythmia gene), in which 10 had definitive phenotypes.
Of the 5 individuals with hypercholesterolemia gene variants (LDLR, APOB), four had existing lipid panels documenting elevated LDL cholesterol (LDL-C) ranging from 120-204mg/dL, with one having a pre-existing risk factor. The last individual was on high-intensity statin treatment, and pre-treated values were unavailable. Only 1 (20%) had significantly elevated LDL-C (>190mg/dL) and was considered to have a definitive phenotype.
Finally, of the 13 individuals with multisystemic gene variants (TTR, GLA, DMD, FBN1, COL3A1), the TTR Val142Ile founder variant was the most common (7; 56%). Four TTR individuals (age range: 44-66) had at least a cardiac MRI and/or amyloidosis scan, in which 1 (25%) was confirmed to have cardiac amyloidosis and signs of neuropathy, while 1 had confirmed neuropathy. Four females (age range: 35-66) had X-linked gene variants (2 DMD, 2 GLA), with both GLA variants being associated with late onset disease. Echocardiography did not show evidence of relevant cardiac disease, although 1 GLA carrier had biochemical abnormalities and a family history of hypertrophic cardiomyopathy. Two individuals with a connective tissue disease gene (FBN1, COL3A1), had normal echocardiography, with the COL3A1 carrier also having normal vascular imaging; however, connective tissue findings were noted.
In total, 20/41 (49%) individuals had a possibly related phenotype related to their cardiovascular variant, while 11 (55%) had definitive phenotype.
Conclusion:
The disease penetrance of cardiovascular gene variants appears to be high, though with notable variability across disease subcategories. Our findings highlight the broad phenotypic spectrum of inherited cardiovascular diseases, and underscore the necessity of comprehensive phenotyping in individuals receiving actionable cardiovascular variants, as approximately half of patients do not have definitive phenotype for their variant.
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