Implications and ramifications of using the CDC tier 1 genetic screening concept in East Asian populations

The US Centers for Disease Control and Prevention defined the Centers for Disease Control and Prevention Tier 1 (CDCT1) genomics applications, advocating mass screening for 3 hereditary conditions with significant public health impacts. On this premise, we investigated how genome sequencing (GS) and ethnic differences affect genetic screening in East Asia. Additionally, we incorporated 2 specific genes, NOTCH3 (HGNC:7883) and GJB2 (HGNC: 4284), linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (MIM: 125310) and hereditary hearing loss (MIM: 220290), respectively, into the study design.

We analyzed GS data from 1454 participants in the Taiwan Biobank (TWB) and 2473 participants from the National Health Research Institute (NHRI). SnpEff, ClinVar, and VarSome were used to identify and annotate pathogenic and likely pathogenic (P/LP) variants in the target genes.

The heterozygote frequencies for P/LP variants in the CDCT1 genes were 2.34% and 1.74% for the TWB and NHRI cohorts, respectively. These heterozygote frequencies were higher than those of the Healthy Nevada Project (1.33%). Familial hypercholesterolemia (MIM: 143890, 144010) accounts for more than 60% of the cases. Individuals (43%) who carried P/LP variants were unaware of their hypercholesterolemia status. Compared with the European and African populations, 7 variants were significantly more frequent in the Taiwanese population (P < .001). Notably, the heterozygote frequencies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy with NOTCH3 NC_000019.10:g.15187315G> A p.(Arg544Cys) were 0.75% and 0.89%, and the frequencies of homozygotes for hereditary hearing loss with GJB2 NC_000019.10:g.15187315G>A p.(Val37Ile) were 0.69% and 1.01%, in the TWB and NHRI cohorts, respectively.

This Asian study underscores the implications of CDCT1 screening and the significance of including population-specific variants. Using a GS approach allows for broader detection of actionable diseases, advancing population-based preventive medicine.