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Published on: September 15, 2018
Novel APOB variant causes familial hypercholesterolemia in multiple unrelated families
Akos Berthold1, Rebecca Miller1, Christopher Jordan1
1Department of Genetics, Inova Health System, Falls Church, VA, USA.
Insights
A novel APOB gene variant, c.9498G>C (p.Lys3166Asn), is linked to familial hypercholesterolemia (FH). This discovery aids in diagnosing FH and understanding its genetic basis.
Area of Science:
- Genetics
- Cardiology
- Biochemistry
Background:
- Familial hypercholesterolemia (FH) is a genetic disorder causing high LDL-c and early atherosclerotic cardiovascular disease (ASCVD).
- Interpreting rare genetic variants in FH, particularly in genes like APOB, remains a diagnostic challenge.
- Established FH genes include LDLR, APOB, and PCSK9.
Purpose of the Study:
- To report a novel APOB variant, c.9498G>C (p.Lys3166Asn), identified in multiple unrelated families with FH.
- To investigate the segregation of this variant within families affected by FH.
- To highlight the importance of collaborative data sharing in genetic variant interpretation for FH.
Main Methods:
- Genetic sequencing to identify the novel APOB variant.
- Segregation analysis within affected families.
- Collaboration with diagnostic laboratories to identify additional cases.
Main Results:
- A novel APOB variant (c.9498G>C, p.Lys3166Asn) was identified in multiple FH families.
- The variant segregated with FH in the proband's family, with all affected individuals carrying the variant.
- Three additional probands with severe hypercholesterolemia were found to carry the same variant.
Conclusions:
- The novel APOB variant (p.Lys3166Asn) is strongly associated with FH.
- Functional studies are required for definitive confirmation of pathogenicity.
- Case reports and data sharing are crucial for advancing genetic diagnosis in FH.
Abstract:
Familial hypercholesterolemia (FH) is a genetic disorder leading to elevated low-density lipoprotein cholesterol (LDL-c) and increased risk for early atherosclerotic cardiovascular disease (ASCVD). While the 3 primary genes (LDLR, APOB, and PCSK9) associated with monogenic FH have been well established, rare variants remain challenging to interpret. We report a novel APOB variant, c.9498G>C (p.Lys3166Asn) in the region of the apolipoprotein B100 that is involved in the binding to the LDL receptor (LDLR). This variant was identified in multiple unrelated families with FH. We initially observed this variant in the proband with severe hypercholesterolemia and early ASCVD. Familial testing showed complete segregation of the variant with FH in the proband's family in all tested individuals with hypercholesterolemia. Further collaboration with diagnostic laboratories revealed 3 additional probands with the same variant and severe hypercholesterolemia. These findings suggest that this variant causes FH; however, functional studies are needed for definitive confirmation. This case underscores the importance of collaborative data sharing in variant interpretation and the role of case reports in enhancing genetic diagnosis for FH.
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