Compound LDLR Mutations with Attenuated FH Phenotype

Key finding

Genetic testing revealed she was **homozygous for a splice-site variant** and **heterozygous for a frameshift variant in LDLR exon 18** — compound biallelic LDLR mutations that should, by textbook standards, produce severe homozygous FH with LDL-C often exceeding 13 mmol/L (500 mg/dL). Instead, her phenotype was attenuated. LDL-C of 5.2 mmol/L is elevated but far below what biallelic LDLR disruption typically produces. No xanthomas. No family history of premature CAD. This genotype-phenotype disconnect means standard clinical criteria for FH (Dutch Lipid Clinic Network Score, Simon Broome) would underestimate her genetic risk. She would be classified as heterozygous FH at most — missing the full severity of her underlying molecular defect. ---

Framework connections: The Fragile Engine

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