Clinical Chemistry
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Clinical Chemistry 53: 1601-1608, 2007. First published July 18, 2007; 10.1373/clinchem.2007.086066
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(Clinical Chemistry. 2007;53:1601-1608.)
© 2007 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Molecular Diagnosis of Wilson Disease Using Prevalent Mutations and Informative Single-Nucleotide Polymorphism Markers

Arnab Gupta1,3,4, Mahua Maulik1,4, Poonam Nasipuri1, Ishita Chattopadhyay1, Shyamal K. Das2, Prasanta K. Gangopadhyay2 The Indian Genome Variation Consortium3, Kunal Ray1,a

1 Molecular and Human Genetics Division, Indian Institute of Chemical Biology, Kolkata, India.
2 Bangur Institute of Neurology, Kolkata, India.
3 Nodal Laboratory, Institute of Genomics and Integrative Biology, New Delhi, India.

aAddress correspondence to this author at: Molecular and Human Genetics Division, Indian Institute of Chemical Biology, 4 Raja S C Mullick Rd., Jadavpur, Kolkata 700 032, India. Fax 91-33-2473-5197; e-mail kunalray{at}gmail.com.

Background: Wilson disease (WD) is an autosomal recessive disorder caused by defects in the ATPase, Cu2+ transporting, ß-polypeptide gene (ATP7B) resulting in accumulation of copper in liver and brain. WD can be thwarted if detected at a presymptomatic stage, but occasional recombination during carrier detection with dinucleotide repeat markers flanking the WD locus may lead to faulty diagnosis. We examined the use of intragenic single-nucleotide polymorphism (SNP) markers to avoid this limitation.

Methods: We prepared genomic DNA from the peripheral blood of Indian WD patients. By use of PCR, we amplified the exons and flanking regions of the WD gene and then performed sequencing to identify the nucleotide variants. We genotyped the SNPs in 1871 individuals by use of the Sequenom mass array system. We made linkage disequilibrium plots using Haploview software.

Results: We identified 1 mutation accounting for 11% (19 of 174) of WD chromosomes among patients in addition to 4 prevalent mutations characterized previously. Among 24 innocuous allelic variants identified, we selected 3 SNPs found to have high heterozygosity (>0.40) for the detection of mutant WD chromosomes. On analyzing these SNPs in 28 test individuals, who were sibs to 17 unrelated WD patients, we obtained unequivocal genotyping in 25 cases (approximately 89%). The remaining 3 cases were genotyped by dinucleotide repeat marker (D13S133).

Conclusion: Sets of SNP markers are highly heterozygous across most world populations and could be used in combination with analysis of prevalent mutations as a comprehensive strategy for determining presymptomatic and carrier sibs of WD patients.






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