**Background:** Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder causing severely elevated low-density lipoprotein cholesterol (LDL-c) and premature atherosclerosis. It is commonly caused by mutations in LDLR, APOB, or PCSK9 genes. In Malaysia, the prevalence of genetically confirmed heterozygous FH (HeFH) is 1 in 427, yet FH remains underdiagnosed and undertreated in primary care. Clinical diagnostic criteria (Simon Broome, Dutch Lipid Clinic Criteria) and the FAMCAT case-finding tool can identify at-risk patients, but genetic testing is not routinely available in Malaysia. This case series reports three FH index cases detected in primary care and subsequently genetically confirmed.
**Methods:** Three patients were identified in primary care from September 2020 to April 2021 as part of a UK-Malaysia joint research study. Demographic data, family history, symptoms (WHO Rose Angina Questionnaire, Edinburgh Claudication Questionnaire), and highest fasting lipid profiles were collected from electronic medical records. Physical examinations for tendon xanthomas and corneal arcus were performed. Patients were clinically diagnosed using Simon Broome criteria, Dutch Lipid Clinic Criteria (DLCC), and FAMCAT relative risk score. Those fulfilling at least one criterion were offered genetic testing after genetic counseling by trained primary care physicians. Venous blood samples were collected, and genomic DNA was extracted. Targeted next-generation sequencing covered exons and untranslated regions of LDLR, APOB, PCSK9, and LDLRAP1 genes. Variants were classified per ACMG guidelines. Primary care physicians delivered results and counseled patients; those with confirmed FH were referred to lipid specialists for up-titration of lipid-lowering therapy and cascade screening of first-degree relatives.
**Key Results:** Case 1: 39-year-old Malay woman with LDL-c 8.6 mmol/L, total cholesterol (TC) 10.4 mmol/L, tendon xanthomas on metacarpophalangeal joints, Achilles tendon, and knees, no corneal arcus. Family history of premature CAD (father had MI at 46, CABG at 47). She fulfilled definite FH by Simon Broome, DLCC score 16 (definite FH), FAMCAT relative risk 32.3. Genetic testing revealed a frameshift c.660del pathogenic variant in LDLR (p.Asp221fs). Case 2: 57-year-old Chinese woman with LDL-c 5.7 mmol/L, TC 8.5 mmol/L, stage 4 corneal arcus (onset in thirties), no tendon xanthomas. Family history of hypercholesterolemia and premature corneal arcus in siblings; mother died of recurrent stroke at 56. She fulfilled possible FH by Simon Broome, DLCC score 14 (definite FH), FAMCAT relative risk 4.4. Genetic testing showed a missense c.10579C>T pathogenic variant in APOB (p.Arg3527Trp). Case 3: 41-year-old Malay man with hypertension, LDL-c 5.4 mmol/L, TC 7.3 mmol/L, no tendon xanthomas or corneal arcus. Mother had stroke at 60. He fulfilled possible FH by Simon Broome, but DLCC score 4 and FAMCAT relative risk 0.6. Genetic testing revealed a missense c.277C>T mutation in PCSK9 (p.Arg93Cys), with conflicting evidence on pathogenicity (possibly benign). All three patients failed to achieve LDL-c target <1.8 mmol/L on statin therapy (atorvastatin 20 mg, simvastatin 20 mg, simvastatin 10 mg, respectively) and were referred to lipid specialists. Cascade screening of first-degree relatives is ongoing.
**Clinical Implications:** This case series demonstrates that primary care physicians can effectively identify FH index cases using clinical criteria and deliver genetic counseling when genetic testing is available. The LDLR mutation (case 1) was associated with the highest LDL-c and most severe phenotype (tendon xanthomas), consistent with literature. The APOB mutation (case 2) showed intermediate LDL-c and corneal arcus, while the PCSK9 mutation (case 3) had the lowest LDL-c and no classic physical findings, suggesting possible benignity. Early detection and treatment with high-dose statins (e.g., atorvastatin) and combination therapy (ezetimibe, PCSK9 inhibitors) are essential to achieve LDL-c targets and prevent premature ASCVD. Cascade screening of first-degree relatives is cost-effective and should be integrated into primary care. Establishment of a national FH registry and clinical practice guidelines in Malaysia would improve awareness and management. Primary care physicians should maintain a high index of suspicion for FH in patients with LDL-c >4.9 mmol/L and collaborate with lipid specialists for optimal care.