OBJECTIVE: To explore the genetic variant spectrum and epidemiological characteristics of Familial hypercholesterolemia (FH) patients in a regional population. METHODS: A retrospective analysis was carried out on exome data from 15 841 unrelated patients undergoing trio-whole exome sequencing and couples undergoing comprehensive carrier screening at the Affiliated Women and Children's Hospital of Ningbo University from January 2022 to June 2025. The analysis focused on FH-associated LDLR, APOB, and PCSK9 genes recommended by the American College of Medical Genetics and Genomics (ACMG) as secondary findings with clinical actionability. Pathogenic and likely pathogenic variants with clear pathogenic effects were reported based on the latest ACMG variant interpretation standards. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: NBFE-2025-KY-178). RESULTS: Through the analysis of 15 841 exome sequencing datasets, 145 FH-associated gene variant carriers were identified, with a carrier rate of 0.92%, and 46 distinct variant sites were detected. Among these, LDLR gene variants accounted for 75.17%, comprising 37 variant sites, with c.268G>A (p.Asp90Asn), c.1747C>T (p.His583Tyr) and c.1879G>A (p.Ala627Thr) being high-frequency variants. APOB gene variants accounted for 22.76%, comprising 6 variant sites, with c.10579C>T (p.Arg3527Trp) being a high-frequency variant. PCSK9 gene variants accounted for 2.07%, comprising 3 variant sites. Three previously unreported variants were identified, including one in the LDLR gene, namely c.394_397delinsGA (p.R132Efs*47), and two in the APOB gene, namely c.10696del (p.Ser3566ValfsTer8) and c.2517del (p.Thr840Leufs*23). The two APOB variant carriers exhibited low levels of low-density lipoprotein cholesterol, consistent with the diagnosis of familial hypobetalipoproteinemia (FHBL). CONCLUSION: Above findings revealed the characteristics of FH-associated gene variant spectrum in a large regional population, which provided evidence-based support for proactive prevention and precision treatment.