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.