Incorporation of genetic testing increases rates of diagnosis for FH
Incorporation of genetic testing significantly increases the number of individuals diagnosed with familial hypercholesterolemia
Introduction and methods
Familial hypercholesterolemia (FH) is typically due to pathogenic variants in APOB, LDLR, PCSK9, and LDLRAP1 and is characterized by elevated LDL-c levels. Patients are at high risk of developing atherosclerotic CVD [1-3]. There are multiple diagnostic criteria for FH, such as the US Make Early Diagnoses Prevent Early Deaths Program Diagnostic Criteria (US MEDPED), Simon Broome criteria and Dutch Lipid Clinic Network (DLCN) criteria [4-7]. US MEDPED takes into account total cholesterol levels and family history of FH. Simon Broome and DLCN criteria also consider physical signs of FH, personal or family history of premature coronary artery disease or hyperlipidemia, and a positive genetic test result. A consensus statement published in the Journal of American Collage of Cardiology (JACC) concerning the utilization of genetic testing for FH recommends genetic testing in adults with LDL persistently ≥250 mg/dL (regardless of family history), in adults with LDL-c persistently ≥190 mg/dL (with family history of hyperlipidemia or premature CAD), and in adults with LDL-c persistently ≥160 mg/dL (with family history of hyperlipidemia and either a personal or family history of premature CAD) . However, even with these criteria and recommendations, FH remains underdiagnosed. A possible explanation for underdiagnosis could be that genetic testing is not incorporated into evaluations. This study compared diagnosis rate before and after genetic testing.
A total of 134 adults were included in the analysis who were seen at the Advanced Lipid Disorders Clinic at the John Hopkins Hospital for FH evaluation and who underwent genetic testing. Pediatric patients and individuals with homozygous FH were excluded. US MEDPED, Simon Broom and DLCN criteria were applied to each patient before and after genetic testing. Genetic testing included sequencing and deletion duplication analysis of APOB, LDLR, PCSK9, and LDLRAP1 genes.
- From in total 134 individuals, 29 had pathogenic or likely pathogenic variants, 90 had negative results and 15 carried a variant of uncertain significance. Of the 29 individuals with pathogenic or likely pathogenic variants, 23 (79%) met the JACC 2018 consensus recommendations for when genetic testing should be offered and 28 (96%) met recommendations for when genetic counseling could be considered.
- Incorporating genetic testing identified 12 additional patients if Simon Broome criteria were used and 14 additional patients if DLCN criteria were used. US MEDPED criteria do not consider genetic test results. However, genetic testing identified 11 additional patients who did not meet the cholesterol level cutoffs. 5 Additional patients (8%) were identified by genetic testing if all three diagnostic criteria were used.
- 35 Individuals met criteria for “definite FH” according to DLCN criteria before genetic testing, of those 15 patients (42%) had positive genetic test results. 30 Individuals met criteria for “definite FH” pregenetic testing using Simon Broome criteria, of which 18 patients (60%) had positive genetic test results. 29 Individuals met criteria for FH using US MEDPED criteria pregenetic testing and of those 18 (62%) had positive genetic test results.
- 43% (n=10) Of the individuals with “probable FH” according to DLCN scores had positive genetic test results and almost a third of individuals with “possible FH” according to Simon Broome criteria had positive genetic test results.
Depending on the criteria used (US MEDPED, Simon Broome or DLCN), incorporation of genetic testing identified 11-14 additional patients with FH, compared to classification based only on clinical criteria. This suggests that family history and a patient’s phenotype alone may not be sufficient for diagnosis of FH.