| Summary: | 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. <i>LDLR</i>, <i>APOB</i>, <i>PCSK9</i>, <i>LDLRAP1</i>, <i>ABCG5</i>, <i>ABCG8</i>, <i>LIPA</i>, <i>LPA</i>, <i>CYP27A1</i>, and <i>APOE</i> genes were analyzed. Only variants annotated as pathogenic (P) or likely pathogenic (LP) using the FH Variant Curation Expert Panel guidelines for <i>LDLR</i> and adaptations for <i>APOB</i> and <i>PCSK9</i> 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 <i>LDLR</i> gene and 1 in the <i>APOB</i> gene. Additionally, 24, 54, and 13 VUS were detected in <i>LDLR, APOB,</i> and <i>PCSK9</i>, 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.
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