A Custom-Made Newborn Screening Test for Wilson's Disease in Puerto Rico.

Background Wilson's disease (WD) is an autosomal recessive progressive, disabling, life-threatening disease. Although early diagnosis and treatment can halt disease progression and reverse disability, diagnosis is often challenging, with a mean diagnostic delay of approximately two years. At least 98% of WD-causing variants are in the  () gene. Identifying mutations that cause WD in Puerto Rico will allow newborn screening for WD, as well as preventive, life-saving treatment. Methodology TaqMan genotyping assays were performed on 174 random volunteers in southwestern Puerto Rico and on three independent WD cases for rs367956522 and rs140708492, single-nucleotide polymorphisms (SNPs) composing a WD-causing haplotype. A polymerase chain reaction followed by Sanger DNA sequencing confirmed the case genotypes. Bioinformatics analyses were performed on polymorphisms present in The 1000 Genomes Project (1KGP) database for Puerto Rico. Results rs367956522 is always inherited together with rs140708492 but not vice versa. The three independent WD cases were homozygous for both SNPs, but the evidence strongly suggested that rs367956522 is the pathogenic variant. The 1KGP database revealed the presence of only one other likely pathogenic variant, rs191312027 (Gly869Arg). Together, both variants may be responsible for causing WD in one of every 14,156 Puerto Ricans. Both are likely of European origin. Conclusions Genotyping probes for both variants are readily commercially available. Thus, rapid, inexpensive newborn screening for rs367956522 and rs191312027 is strongly recommended. Although these two variants may account for all or the vast majority of WD cases in Puerto Rico, other polymorphisms described or not described in this study might also be pathogenic.