Genetic screening of malay familial hypercholesterolemia patient for LDLRAP1/PCSK9/APOB mutations via whole exome sequencing
Abstract Background Familial Hypercholesterolemia (FH) is a hereditary lipid disorder with an autosomal dominant genetic inheritance, characterized by high low-density lipoprotein cholesterol (LDL-C) levels and premature atherosclerosis. An elevated cholesterol level is correlated with a high risk o...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SpringerOpen
2025-03-01
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| Series: | Egyptian Journal of Medical Human Genetics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s43042-025-00673-z |
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| Summary: | Abstract Background Familial Hypercholesterolemia (FH) is a hereditary lipid disorder with an autosomal dominant genetic inheritance, characterized by high low-density lipoprotein cholesterol (LDL-C) levels and premature atherosclerosis. An elevated cholesterol level is correlated with a high risk of cardiovascular disease (CVD). FH-causing variants are commonly found in LDLR, APOB, PCSK9, and LDLRAP1, with LDLR accounting for about 80% of the prevalence. In Malaysia, about 1 in 100 people are affected by FH, which has a prevalence of 47.7% among Malaysian adults, with 38.6% of cases going undiagnosed. Hence, early detection can greatly lower the risk of CVD. Methods In this case study, a 41-year-old female suspected of having FH underwent screening using a whole exome sequencing (WES)-trio-based approach to determine the FH variants involved. WES was performed on the proband and her parents via the MGI genome sequencing platform, and the variants were annotated with wANNOVAR, followed by FH-associated variant discovery using Phenolyzer. The variants were further validated in the proband, father, mother, and two siblings using the Sanger sequencing platform. Given the multifactorial nature of variant effects on protein structure, it remains unclear which specific alterations in protein structure are significant in FH. Thus, the wild-type and mutant structures were compared to investigate the impact of the variants on protein structure and interaction. Results Seven monogenic missense variants among the first-tier genes were discovered in the proband, in which PCSK9:c.G1420A, PCSK9:c.G2009A, and APOB:c.A6937G were inherited from both parents, LDLRAP1:c.T604C and APOB:c.G13013A were passed from the mother, and APOB:c.C8216T and APOB:c.C1853T from father. Although reported as benign, the variants PCSK9:c.G1420A, LDLRAP1:c.T604C, APOB:c.A6937G, and APOB:c.C1853T were found to destabilize protein structure and interactions, with predicted stability changes of − 1.0 < ΔG < − 0.1 and interaction affinity changes of − 2.0 < ΔG < − 0.1. This suggests their potential roles as FH-causing variants or at the very least, possible risk variants in FH. The proband inherited two benign variants, LDLRAP1:c.T604C and APOB:c.G13013A, from the mother, who has a family history of cardiovascular disease. These variants are suggested as potential risk factors for FH, as the same variants were also present in the two siblings diagnosed with FH. Conclusion In conclusion, identifying variants in the proband is essential for cascade screening and early interventions to reduce the risk of CVD in FH. |
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| ISSN: | 2090-2441 |