Population genomics and disease risk of primary cutaneous amyloidosis: A prominent genodermatosis of Southeast Asia

BACKGROUND: Primary Cutaneous Amyloidosis (PCA) is a skin-limited disorder more common in Southeast Asian. Previous studies have identified mutations located in a fibronectin type III-like repeat domain of OSMR gene, including p.G513D (c.1538G > A). METHODS: To investigate the genetic background of PCA, we recruited a consecutive series of 91 unrelated PCA patients, and subjected to whole-exome sequencing (WES) for genomic analysis. We also analyzed population genomic data from Taiwan, Japan, Singapore, Vietnam, Brazil, and the USA to evaluate the distribution of OSMR variants across different countries and ethnicities. A genetic screening program was conducted on 37,770 individuals at a hospital using the Taiwan Precision Medicine Initiative array (TPMI). RESULTS: The OSMR variant, c.1538G > A p.G513D, was identified in 24.18% (22/91) of patients with PCA, compared to only 2.61% (39/1,495) in the control group from Taiwan Biobank (OR = 11.90; 95% CI: 6.69-21.17; p < 0.0001). Its proportion was higher among East Asians, particularly in Taiwanese, Vietnamese, and Chinese Singaporeans, and nearly absent in European or Japanese populations. A hospital-based genetic screening revealed that 2.5% (944/37,770) of individuals carried the OSMR p.G513D variant. Notably, 57.14% (4/7) of homozygous individuals were diagnosed with PCA, compared to 1.39% (13/937) of heterozygous individuals (OR = 94.77; 95% CI: 19.24-466.70; p < 0.0001). CONCLUSION: These findings establish OSMR p.G513D as a population-specific risk allele for PCA and highlight the need for ancestry-aware genetic screening in Southeast Asians.