Laboratory and clinical evaluation of a microarray for the detection of ATP7B mutations in Wilson disease in China

Abstract

Background and objective Wilson disease (WD) is an autosomal recessive copper metabolic disorder caused by mutations in ATP7B. Sanger sequencing is currently used for ATP7B variant identification. However, the ATP7B gene contains 21 exons, which makes sequencing of the entire gene both complex and time‐consuming. Therefore, a simpler assay is urgently needed. Methods We performed a laboratory and clinical evaluation of an oligonucleotide microarray for the detection of 24 ATP7B recurrent mutations (except p.P992L) in Chinese patients with WD. Results The accuracy of the microarray was evaluated by screening for ATP7B mutations in 126 patients including 106 suspected WD samples and 20 patients with other liver diseases as negative control. Results were confirmed by Sanger sequencing. We established a reliable microarray system for the rapid detection of the 24 ATP7B mutations, with a sensitivity of 30 ng/test genomic DNA and specificity of 100% for all loci; the coefficient of variation in repeatability tests was <10%. Clinical evaluation showed an overall concordance between the microarray detection and sequencing of 100%, and 81.13% (86/106) of suspected WD cases showed ATP7B mutations by microarray detection. Microarray and Sanger sequencing identified p.R778L (50.94%), p.A874V (17.92%), p.P992L (11.32%), p.V1106I (11.32%), and p.I1148T (6.60%) as the most common mutations in WD patients. Conclusions Our microarray system is customizable and easily used for high‐throughput detection of certain recurrent ATP7B mutations, providing a simpler method suitable for WD genetic diagnosis in China.

Sorting Intolerant from Tolerant and PolyPhen-2 Algorithms: A Variation in Exon 14 of ATP7B Gene among 4 West Iraqi Families with Wilson’s Disease

“…As a result, the disease's symptoms will lessen, and no further medical attention will be required. It is believed that WD is more prevalent in rural regions than urban ones due to the high rate of consanguinity among rural populations [20]. The study's contrary conclusion may be relevant to the kinds of medical treatments.…”

The mutation spectrum and ethnic distribution of Wilson disease, a review

“…It is unknown why a particular genotype is not associated with a specific behavior of the disease. In the most prevalent variant of East Asia, some articles report that Wilson's patients with the R778L variant present with an earlier onset of disease and predominantly hepatic symptoms [ 13 , [15] , [16] , [17] , [18] , [19] ]. Patients with the H1069Q variant, which is the most prevalent variant in Europe, North America, and North Africa, show a complete range of clinical manifestations; this mutation is not predominantly associated with a late or neurologic presentation [ [20] , [21] , [22] , [23] ].…”