👤 Min-Ji Charng

The genetic and phenotypic spectrum of homozygous familial hypercholesterolemia (HoFH) in Han Chinese populations remains insufficiently defined. To delineate the nationwide genetic and clinical features of HoFH in Taiwan, including true HoFH, double heterozygous FH (HeFH), and compound HeFH. Patients with clinically diagnosed probable or definite FH enrolled in the Taiwan FH Registry who underwent genetic testing between 2006 and 2025 were analyzed. A comprehensive workflow integrating microarray assay, mass spectrometry, targeted next-generation sequencing, and multiplex ligation-dependent probe amplification was implemented. Variants were classified using American College of Medical Genetics and Genomics guidelines. Of 1479 screened individuals, 63 were genetically confirmed to have HoFH (mean age, 32.8 ± 22.7 years), including 28.6% with atherosclerotic vascular disease. The cohort comprised 14 true HoFH (including homozygous APOB variants), 6 double HeFH, and 43 compound HeFH. The highest documented low-density lipoprotein cholesterol (LDL-C) levels were 357.3 ± 123.5 mg/dL in true HoFH, 347.3 ± 39.2 mg/dL in double HeFH, and 443.5 ± 170.9 mg/dL in compound HeFH. The most frequent genotypes were LDLR [IVS2+4A>T];[IVS2+4A>T] in true HoFH, [APOB p.R3527W];[LDLR IVS2+4A>T] and [APOB p.R3527W];[LDLR p.D90N] in double HeFH, and LDLR [p.D90N];[p.C329Y] in compound HeFH. Patients with double HeFH had lower LDL-C levels and fewer xanthomas than those with LDLR homozygosity or compound mutations, while individuals with homozygous LDLR exon deletions/duplications had the highest LDL-C levels. This nationwide study provides the first comprehensive genetic and clinical characterization of HoFH in Taiwan. Our findings highlight the importance of precise genetic diagnosis and early detection strategies in improving outcomes for this high-risk population. Show less

Whole exome sequencing (WES) is a recently developed method for discovering rare mutations associated with hereditary disorders. However, the feasibility and utilization of this method in identifying familial hypertriglyceridemia is not well known. The purpose of the study was to identify the genetic locus that causes hypertriglyceridemia and assess its prevalence in Taiwanese subjects with hypertriglyceridemia. We performed WES among two individuals with hypertriglyceridemia and one control subject in an index family (22 members). Based on the WES findings, we extended the study to genotype 65 unrelated adult index patients with a fasting serum triglyceride level of ＞ 500 mg/dL and 125 normal controls using polymerase chain reaction. Using WES alignment, variant calling and annotation, 15 presumptive causal variants were initially identified, including 13 cases by the autosomal dominant model and two cases by the autosomal recessive model. Only APOA5 c.553 G ＞ T (rs2075291), resulting in the amino acid mutation Gly185Cys, co-segregated well with hypertriglyceridemia in terms of autosomal recessive inheritance (homozygote TT: mean triglyceride level: 1,071 mg/dL vs non TT (GT and GG): mean triglyceride level: 118 mg/dL; p ＜ 0.001) in the index family. In the unrelated cohorts, the frequency of the TT genotype of rs2075291 was 12.3% in the hypertriglyceridemic group; however, no TT genotype was found in the control group. Our results demonstrate that WES is feasible for identifying the genetic locus that causes hypertriglyceridemia. The TT genotype of APOA5 c.553G ＞ T acts as an important indicator of hypertriglyceridemia in patients in Taiwan. Show less

Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder associated with sudden death, heart failure, and stroke. The aim of the present study was to evaluate the prevalence and types of mutations in symptomatic patients with HCM in Taiwan. Thirty-eight HCM index patients (mean age 60±16 years) underwent systematic mutation screening of eight sarcomeric genes: β-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), troponin T (TNNT2), troponin I (TNNI3), myosin ventricular regulatory light chain 2 (MYL2), myosin ventricular essential light chain 1 (MYL3), α-tropomyosin (TPM1), and cardiac α-actin (ACTC), using direct DNA sequencing. In silico programs predicted damaging amino acids. In the positive families, genotype-phenotype correlation studies were done. Overall, 13 mutations were identified in 13 index patients (34.2%). The three most frequently mutated genes were MYH7, MYBPC3, and TNNT2. One patient carried double mutations. Five mutations (MYH7 R147S; MYBPC3 R597Q; MYBPC3 W1007R; TNNI3 E124Q; MYL3 R63C) were novel; all were missense mutations. Analysis using in silico tools showed near consensus to classify these five novel mutations as pathological. Family pedigree analysis showed the presence of cosegregation in at least two affected members in each proband family, but incomplete penetrance in young family members with a positive genotype. We identified 13 HCM pedigrees, including 5 carrying novel mutations and 1 with a double mutation. The three most commonly mutated genes were MYH7, MYBPC3, and TNNT2. These results, together with genetic counseling, could lead to earlier diagnosis and better management of family members at risk of HCM. Show less