Spectrum and classification of variants with clinical correlation in children with Wilson disease.

OBJECTIVES

To study the spectrum and classification of variants in Iraqi children with Wilson disease by direct gene sequencing with clinical correlation.

METHODS

Fifty-five unrelated children with a clinical diagnosis of Wilson disease (WD) were recruited. Deoxyribonucleic acid was extracted from peripheral blood samples, and variants in the gene were identified using next-generation sequencing.

RESULTS

Seventy-six deleterious variants were detected in 97 out of 110 alleles of the gene. Thirty (54.5%) patients had 2 disease-causing variants (15 homozygous and 15 compound heterozygous). Twelve (21.8%) patients had one disease-causing variant and one variant of uncertain significance (VUS) with potential pathogenicity. Thirteen (23.6%) patients were carriers of a single disease-causing variant. The most frequent variants, c.3305T>C and c.956delC, were detected in 4 alleles each, followed by c.3741-3742dupCA and c.3694A>C, which were detected in 3 alleles each. Among the 76 variants, 42 were missense, 13 were stop-gain, 9 were frameshift, 1 was an in-frame deletion, and 11 were intronic variants. Notably, the globally common variant H1069Q was not detected in this study.

CONCLUSION

The mutational spectrum of in the Iraqi population is diverse, despite the high rates of consanguinity. It differs from that of neighboring countries. We provided evidence for ten VUS to be reclassified as deleterious, raising questions about the diagnostic criteria for patients with higher Leipzig scores and a single deleterious variant.