Genetic Characteristics of Latvian Patients with Familial Hypercholesterolemia: The First Analysis from Genome-Wide Sequencing.

BACKGROUND: There is limited data on the genetic characteristics of patients with familial hypercholesterolemia (FH) in Latvia. We aim to describe monogenic variants in patients from the Latvian Registry of FH (LRFH). METHODS: Whole genome sequencing with 30× coverage was performed in unrelated index cases from the LRFH and the Genome Database of Latvian Population. LDLR, APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, LIPA, LPA, CYP27A1, and APOE genes were analyzed. Only variants annotated as pathogenic (P) or likely pathogenic (LP) using the FH Variant Curation Expert Panel guidelines for LDLR and adaptations for APOB and PCSK9 were reported. RESULTS: Among 163 patients, the mean highest documented LDL-cholesterol level was 7.47 ± 1.60 mmol/L, and 79.1% of patients had LDL-cholesterol ≥6.50 mmol/L. A total of 15 P/LP variants were found in 34 patients (diagnostic yield: 20.9%): 14 in the LDLR gene and 1 in the APOB gene. Additionally, 24, 54, and 13 VUS were detected in LDLR, APOB, and PCSK9, respectively. No P/LP variants were identified in the other tested genes. CONCLUSIONS: Despite the high clinical likelihood of FH, confirmed P/LP variants were detected in only 20.9% of patients in the Latvian cohort when assessed with genome-wide next generation sequencing.

Latvian registry of familial hypercholesterolemia: The first report of three-year results.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) was rarely diagnosed in Latvia before 2015, when the Latvian Registry of FH (LRFH) was established. Here, we report the first experience of the LRFH over three years (2015-2017). METHODS: The LRFH is an ongoing nationwide, dynamic, long-term prospective cohort. The diagnosis of FH was assessed using the Dutch Lipid Clinic Network (DLCN) criteria. Cascade screening of first-degree relatives using age- and sex-specific percentiles of low-density lipoprotein cholesterol (LDL-C) was performed in relatives of patients with definite and probable FH. RESULTS: Among the 416 individuals included in the LRFH, 181 patients were diagnosed with FH (140 index cases and 41 relatives) and 151 with possible FH (not analysed in this report). The mean age was 51.3 ±â€¯14.1 years, 38.1% (n = 69) were men and 35.4% (n = 64) had a history of premature coronary heart disease. Only 54.1% (n = 98) of patients were on any lipid-lowering therapy before inclusion in the LRFH. The maximal statin dose was used by 23.2% (n = 42), and only 4.4% (n = 8) had their LDL-C levels below the goal. The initial mean total and LDL-C levels were 7.7 ±â€¯2.2 and 5.5 ±â€¯2.1 mmol/L, respectively. In a subgroup of patients (n = 49) with follow-up, LDL-C levels were reduced from 6.1 ±â€¯2.1 to 3.6 ±â€¯1.7 mmol/L (p < 0.001). CONCLUSIONS: An estimated 2.3% of FH patients in Latvia were diagnosed within three years. The vast majority of FH patients were under-recognized and poorly treated before their inclusion in the LRFH. Specialized care of FH patients within the frames of the registry substantially improved the management of this high-risk group.