A cautionary tale: Is this APOB whole-gene duplication actually pathogenic?

A 22-year-old woman presented with elevated low-density lipoprotein (LDL) cholesterol and clinically suspected familial hypercholesterolemia. Initial genetic analysis by Sanger sequencing found no causal variants in LDLR or other familial hypercholesterolemia genes. More than a decade later, her 9-year-old daughter was also found to have elevated LDL cholesterol. Re-analysis using current genetic methodology detected a novel whole-gene duplication of APOB in both individuals, which was tentatively assumed to explain their elevated LDL cholesterol based mainly on biological plausibility. However, on further assessment with cascade screening and cosegregation analysis involving multiple family members, the APOB duplication was eventually discounted as being causative. This case illustrates the risk of assuming pathogenicity of a novel genetic variant without undertaking corroborative diagnostic measures. It further highlights the time and skill required for accurate variant analysis and emphasizes the challenges faced by clinicians who are increasingly expected to rapidly interpret such results without sufficient time or resources to pursue supportive or corroborating evidence.