Variable phenotype associated with compound LDLR gene mutations in familial hypercholesterolemia patients: Case series and clinical implications

Rationale: Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder with an extremely elevated level of low-density lipoprotein (LDL) cholesterol (LDL-C) and accelerated premature coronary artery disease (PCAD). It is primarily caused by a single pathogenic variant of the LDL receptor ( LDLR ) gene. This report presents 2 rare and unrelated cases of HoFH with compound LDLR mutations. These 2 individuals presented with atypical clinical features and demonstrated variable degrees of hypercholesterolemia. Patient concerns: Case 1 is a 36-year-old Malay woman identified during family cascade screening with a pretreated LDL-C of 8.5 mmol/L and a strong family history of PCAD. Case 2 is a 58-year-old Indian woman discovered to have a pretreated LDL-C of 5.2 mmol/L during routine health screening, without a significant family history of hypercholesterolemia or PCAD. Neither patient demonstrated tendon xanthomas or other lipid stigmata. Diagnoses: Both patients underwent lipid profiling and targeted next-generation sequencing of FH-related genes ( LDLR , APOB , PCSK9 , ABCG5 , and ABCG8 ). Two novel LDLR variants were identified in exon 18: c.2548-1_2548delGAinsTC (pathogenic) and c.2556_2557insTCAGTCTGG (p.Leu853Serfs*12; likely pathogenic) and classified according to American College of Medical Genetics and Genomics guidelines. Case 1 was homozygous for both variants, while Case 2 was homozygous for the splice-site variant and heterozygous for the frameshift variant. Interventions: Both patients received guideline-directed lipid-lowering therapy and ongoing cardiovascular risk management. Outcomes: Despite biallelic LDLR variants, both patients demonstrated relatively milder hypercholesterolemia and absence of classical HoFH stigmata. Lessons: The LDLR variants located in exon 18 affecting the cytoplasmic tail domain may be associated with attenuated clinical expression. Recognition of genotype–phenotype variability is crucial for accurate diagnosis, risk stratification, and individualized management of HoFH.