Submission Details

The relationship between APOB and familial hypobetalipoproteinemia was assessed using the ClinGen gene-disease clinical validity framework, as of February 5, 2020. Variants in APOB were first reported in relation to familial hypobetalipoproteinemia (FHBL) in 1988 (Young et al, PMID 3399894; Collins et al, PMID 2843815). FHBL is characterized by plasma LDL-cholesterol that are <5th percentile. The condition is inherited in a semi-dominant (co-dominant) manner and is typically caused by variants in APOB that result in the production of truncated forms of apoB100, a structural component of very low density lipoproteins (VLDL) and low density lipoproteins (LDL). Heterozygotes are usually asymptomatic but may develop hepatic steatosis. Homozygotes have extremely low LDL-cholesterol levels and may have symptoms varying from none to severe neurological and gastrointestinal dysfunction (For reviews, see PMIDs 1977530, 8527219, 12639976, 15308601, 15818469, 24751931). Over 60 unique variants in APOB in individuals with hypobetalipoproteinemia have been reported (PMID 22588666). The majority are nonsense and frameshift variants resulting in truncated forms of apoB. However, missense and small inframe deletions have also been reported (Burnett et al, 2003 PMID 12551903; Magnolo et al, 2016, PMID 26825690). Eleven unique variants in this gene were curated from six publications in 8 monoallelic and 2 biallelic probands (Collins et al, 1988, PMID 2843815; Farese et al, 1992, PMID 1527480; Huang et al, 1992, PMID 1770316; Burnett et al, 2003 PMID 12551903; Magnolo et al, 2016, PMID 26825690; Rimbert et al, 2016, PMID 27179706). Segregation evidence from two large families was also curated (Farese et al, 1992, PMID 1527480; Burnett et al, 2003 PMID 12551903). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the well characterized function of apoB (reviewed in Whitefield et al, 2004, PMID 15308601), expression of the gene in liver (https://gtexportal.org/home/gene/APOB), functional alteration experiments (Srivastava et al, 1999, PMID 10224159), and animal models (Kim et al, 1998, PMID 9502790; Chen et al, 2004, PMID 13130124). Additional experimental evidence to support the gene-disease relationship is available in the literature but the maximum experimental evidence score (6 points) has been reached. Of note, this gene has also been implicated in familial hypercholesterolemia (FH); the clinical validity of APOB-FH has been assessed separately by ClinGen. In summary, APOB is definitively associated with FHBL. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Expert Panel. LUMPING AND SPLITTING CONSIDERATIONS: In OMIM, APOB is associated with two disease entities – Hypercholesterolemia, familial, 2 (MIM# 144010) and hypobetalipoproteinemia (MIM# 615558). Per the criteria outlined by the ClinGen Lumping and Splitting Working Group, there are differences in the molecular mechanism and phenotypic presentation for these conditions. Missense variants in the LDL-receptor binding domain of apoB impair binding of LDL to the LDL receptor, causing hypercholesterolemia and premature coronary artery disease, the primary features of FH. In contrast, variants resulting in reduced secretion of APOB (mainly nonsense and frameshift variants) cause familial hypobetalipoproteinemia, which is characterized by hypocholesterolemia and resistance to atherosclerosis. Therefore, these two disease entities have been curated separately for their relationship with APOB.