Phenotypic vs. genetic cascade screening for familial hypercholesterolemia: A case report

Area of Science:

• Cardiovascular Genetics
• Metabolic Disorders

Background:

• Familial hypercholesterolemia (FH) is a common autosomal dominant disorder leading to premature cardiovascular disease due to elevated low-density lipoprotein cholesterol (LDL-C).
• Despite available treatments and genetic diagnostics, FH remains significantly underdiagnosed globally.
• Cascade screening, typically based on clinical data, is a cost-effective strategy for FH identification and cardiovascular disease prevention.

Observation:

• A 48-year-old index patient presented with severe hypercholesterolemia, premature atherosclerosis, and a novel low-density lipoprotein receptor (LDLR) gene variant.
• Phenotypic cascade screening identified three affected relatives (daughter, two grandsons).
• Genetic screening excluded FH in one grandson, highlighting its precision.

Findings:

• Genetic cascade screening proved more effective than phenotypic screening alone in accurately diagnosing FH.
• This case provides the first detailed phenotypic description of patients with the likely pathogenic LDLR-p.K223_D227dup variant.

Implications:

• Genetic cascade screening is crucial for accurate and efficient FH diagnosis.
• Early identification and intervention can prevent severe cardiovascular events in FH patients.
• Understanding genotype-phenotype correlations, like with the LDLR-p.K223_D227dup variant, refines FH diagnosis and management.