Wilson’s disease (WD, OMIM #277900), an autosomal recessive disorder characterized by abnormal copper accumulation and related toxicities, is caused by mutations in the
ATP7B gene (OMIM *606882) [
1]. The
ATP7B gene is located on 13q14.3 spanning ~ 100 kb, including 21 exons and 20 introns; it encodes a transmembrane copper-transporting P-type ATPase of 1465 amino acids, which plays a crucial role in maintaining body copper homeostasis and is involved in copper transport into the plasma by ceruloplasmin as well as copper excretion from the liver [
2‐
4].
ATP7B gene mutations lead to ATP7B protein dysfunction, which in turn causes accumulation of copper in the liver, brain, kidneys and corneas, with a wide range of clinical symptoms, including hepatic disorders, neuronal degeneration of the brain, and Kayser-Fleischer rings at the corneal limbus [
5,
6]. The prevalence of WD is estimated at 1 in 30,000, and the heterozygous carrier rate approximates 1 in 90 in many populations [
7,
8]. Without timely diagnosis and treatment, WD can be fatal [
9]. Early detection and intervention is critical in preventing disease progression and irreversible sequelae. Genetic testing for the detection of biallelic
ATP7B mutations do not only help diagnose WD, but can be also used for prenatal screening. About 540 disease-causing variants have been reported in
ATP7B according to the HUGO database, and are mostly point mutations and small insertions or deletions distributed in all exons/introns (
http://www.wilsondisease.med.ualberta.ca/database.asp). Screening of all exons and flanking intronic regions for
ATP7B mutations is usually performed by direct sequencing, e.g. Sanger sequencing and next-generation high-throughput sequencing. However, mutations are identified in only one allele or none in a substantial number of WD patients [
10]. A possible reason could be that partial gene deletions of one or more exons are not detected by current methods, for example c.4021 + 87_4125-2del2144, c.51 + 384_1708-953del8798, and c.52-2671_368del3039 of the
ATP7B gene [
11‐
13]. For unexplained WD cases, in whom no or one allele is mutated, detecting partial or whole gene deletions/duplications by MLPA assay, QPCR, and other methods is required. Here we report a novel 43-bp deletion by direct Sanger sequencing of all exons in the
ATP7B gene, which is by far the biggest exonic deletion within a single exon of the
ATP7B gene detected in a WD patient. Meanwhile, we comprehensively analyzed the possible mechanisms underlying the formation of this deletion mutation, and a replication-based mechanism named fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) seems to explain it clearly [
14‐
16].