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Implications and Ramifications of Using the CDC Tier 1 Genetic Screening Concept in East Asian Populations

Health Services and Implementation
  • Primary Categories:
    • Genomic Medicine
  • Secondary Categories:
    • Genomic Medicine
Introduction:
The CDC’s office defines the Centers for Disease Control and Prevention Tier 1 (CDCT1) genomics applications, advocating mass screening for three hereditary disease conditions with significant potential impacts on public health. Two recent cohort studies in the U.S. have investigated a range of genetic risks by screening for hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), and familial hypercholesterolemia (FH). With the CDCT1 genetic screening concept, we integrated two Taiwanese population-specific genes, NOTCH3 and GJB2, which were related to Cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL) and hereditary hearing loss into our study. However, the genetic risks associated with these relatively common medical conditions and their screening yields remain unknown for the Taiwanese population and East Asian countries. 

Methods:
We analyzed the whole genome sequence (WGS) data of 1,454 participants from the Taiwan Biobank (TWB) and 2,473 participants from the National Health Research Institutes (NHRI) cohort to investigate pathogenic and likely pathogenic (P/LP) genetic variants of the CDCT1 genes, NOTCH3, and GJB2, as annotated by SnpEff, ClinVar, and VarSome. 

Results:
In the TWB and NHRI cohorts, we found a combined carrier rate of 1.44% and 1.09% for P/LP genetic variants of HBOC, LS, and FH; 0.75% and 0.89% for CADASIL; 18.36% and 19.53% of hereditary hearing loss. Among these carriers, we identified 10 P/LP variants of BRCA2, MSH2, APOB, LDLR, NOTCH3, and GJB2, with allele frequencies higher than 0.1%. Comparing our results with those available from the gnomAD, SG10K, and TogoVar databases, we found that five variants (BRCA2, c.8954-5_8954-2del; MSH2, p.Arg929Ter; ApoB, p.Arg3527Tep; GJB2, p.Val37Ile, and p.His100ArgfsTer14) were present higher allele frequency in individuals with Chinese and Malay ethnicity, and other five variants (BRCA2, p.Ala2786Thr; MSH2, p.His839Arg; LDLR, p.Asp90Asn; NOTCH3, p.Arg544Cys; GJB2, p.Leu79CysfsTer3) were only present in individuals with Chinese ethnicity. Furthermore, using the Healthy Aging Longitudinal Study in Taiwan (HALST) and the TWB long-term cohorts, we have identified carriers of FH variants and confirmed that they have higher risks in cardiovascular disease and total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels than the average. Only 40% of these individuals took the cholesterol-lowering medication in the HASLT cohort, and 37.5% were unaware of FH in the TWB cohort. 

Conclusion:
Our study represents the first adoption of CDCT1 genetic screening in Asia and proves its portability and ramifications to East Asian populations. Taking a transethnic comparison, we have identified population-specific variants that can be used to target at-risk individuals who might benefit from early detection and timely treatment. Our studies should facilitate the use of genomic profiling for implementing community-based preventive medicine, and this approach should empower people to manage their disease risks preemptively.

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