Genetic sequencing is a vital tool for discovering new genetic mutations, researchers report in a case study of a patient with Wilson disease (WD) published in the European Journal of Case Reports in Internal Medicine.

WD, an autosomal recessive disorder of copper metabolism, is characterized by the accumulation of copper in the tissue resulting in neurological, hepatic, and/or psychiatric symptoms. Studies have identified the fundamental genetic defect causing WD within the ATP7B gene by mapping it to chromosome 13q14.1. Reportedly, over 600 mutations have been discovered until now. Most of the patients carry 2 different mutations. 

In this study, the research team assessed a 70-year-old man experiencing action tremors in the far upper extremity and having worse handwriting and micrographics. The patient had no family history of WD, and his parents were not consanguineous.

Read more about Wilson disease diagnosis

The research team performed molecular genetic analyses of the ATP7B gene. Results indicated that in heterozygosis, variant c.98T>C p(Met33Thr) was observed in exon 2 of the gene. The observed variant replaced methionine with threonine at codon 33 of the translated protein, which is contemplated as a rare variant (gnomAD: 0.06%) and was reported as a variant of vague meaning in the ClinVar database.

Moreover, variant c.2224G>A (Val742Ile) was observed in exon 8 of the gene in heterozygosis. The second observed variant replaced valine with isoleucine at codon 742 of the translated protein. This variant is considered a novel variant that is not found in population databases consulted during the study. Furthermore, it has not been explained in individuals with ATP7B-associated disease.

“We report the case of an elderly man diagnosed with late-onset WD with mild neurological symptoms only and a new mutation in the ATP7B gene. We attribute the mild presentation of the disease to a missense-type mutation leading to low penetrance,” the authors wrote. Possibly, insertion/deletion and nonsense mutations change the reading frame of ATP7B, resulting in the shortening of the protein, thus leading to relentless and earlier disease. 

It is reported that even though most patients with WD show symptoms between the ages of 5 and 35 years, many patients as young as 3 years and as old as 84 years have been reported to have the disease. Hence, it is suggested that the patient’s age should not rule out a WD diagnosis. 

References

Villander Barros de Oliveira Sá M, Siqueira Pacheco FJ, Carvalho Figueredo JL, et al. New ATP7B gene mutation in a Brazilian patient with Wilson disease. Eur J Case Rep Intern Med. Published online December 1, 2022. doi:10.12890/2022_003655