Background <p>Expanded carrier screening (ECS) has emerged as an established and efficient approach for identifying carriers of recessive inherited disorders. However, its application and associated carrier frequency data remain scarcely documented in the population of Shandong Province, China. This study aimed to perform ECS in this regional cohort to characterize the carrier spectrum of recessive disease and to facilitate improved reproductive counseling through the early detection of high-risk fetuses.</p> Methods <p>A total of 3929 individuals from Shandong Province, comprising 1923 couples and 83 single individuals, underwent ECS targeting 222 genes. Screening was performed using next-generation sequencing supplemented with polymerase chain reaction-based methods.</p> Results <p>A total of 3010 pathogenic/likely pathogenic (P/LP) variants were detected, with an average of 0.77 variants per individual. The overall carrier frequency was 53.02% (2083/3929), and 18.20% (715/3929) of participants carried multiple disease-associated variants. Among all 3929 participants, 46 couples carried P/LP variants of the same autosomal recessive disorders and 27 women carried X-linked (XL) disorders. The overall frequency of at-risk couples (ARCs) was 3.03%.</p> Conclusion <p>This study provides preliminary data on carrier frequencies for 259 monogenic disorders in the Shandong population. The identified ARCs received reproductive during clinical follow-up. These findings contribute to generating evidence for wider clinical application of ECS.</p>