Genotype-phenotype correlation in Wilson disease.

Ever since the independent elucidation of the principles of heredity by the likes of Hugo de Vries and Carl Correns in the early 20th century and the subsequent rediscovery of Gregor Mendel’s writings from a century earlier, one of the fundamental challenges in human genetics has been linking the clinical phenotype of disease with a genotype or genotypes. It has only been since the 1980s that the technology has existed to connect the DNA of genes directly with human disease, but since then well over a thousand genes responsible for human diseases have been identified. This, of course, includes the gene that is defective in Wilson disease (WD), ATP7B on the long arm of chromosome 13 (13q14.3-q21.1). Even for simple Mendelian disorders the phenotype is usually manifest as a range or spectrum. For WD this can be expressed by the phenotypic classification proposed by Peter Ferenci et al. of clinical presentation based on the presence of symptomatic liver disease, neuropsychiatric disorders, and other features (hematologic, renal, etc). In this edition of the journal a group from Lebanon presents their data and argues that the homozygous mutations in exon 18 of ATP7B identified in the two families studied and in other individuals described in the literature are likely to develop predominantly liver disease as their initial presenting feature. The basis for this assertion is that hepatic disease was seen in 4 of the 5 WD patients from the 2 sibships, with the fifth subject identified by family screening before clinically obvious disease. Furthermore on an extensive search of the published literature another 20 cases of WD were found with homozygosity for an exon 18 mutation of which 80% had a hepatic presentation of WD. The authors go onto discuss that exon 18 includes the highly evolutionary conserved motif for the ATP hinge region of the WD protein and that the result of each missense mutation is a nonconservative amino acid substitution. Although there is no physical evidence to date, the assumption is that mutations in this region of the gene are likely to significantly affect protein structure and therefore function. The authors do a fine job at explaining the difficulty in establishing a clear link between WD phenotype and ATP7B mutations siting the large number of mutations identified in this gene, the predominance of compound heterozygosity in WD patients and the significant phenotypic variability between patients with the same mutations even within families. Does a hepatic presentation mean more severely deranged ATP7B function? This has certainly been the working assumption in this paper while recognizing that other factors must be at play in the overall phenotypic expression of WD in individuals. These other factors may include environmental factors such as nutritional copper intake, infectious diseases and drugs and toxins, modifier genes, and other epigenetic factors. It has been suggested that ‘‘hepatic’’ phenotypes are more likely with nonsense or frameshift mutations whereas ‘‘milder’’ neurologic presentations increase with missense mutations, but as the authors of this paper point out several other publications have failed to confirm this assertion. The authors of the paper attempted to control for the effect of polymorphic variations in ATP7B gene by demonstrating shared single nucleotide polymorphisms across 5 other exons of the ATP7B gene. However, these variations are not uncommon in normal population and therefore, it would require much larger study cohort to see if they are contributing to the clinical phenotype in WD. Although as earlier stated the search for genotype-phenotype correlation has been a fundamental aim of human genetics since its inception as a branch of science, what is the purpose of this search? The first is for accurate and early (even presymptomatic screening) diagnosis if other nongenetic approaches are less than water tight. This is particularly true if a clinical phenotype is shared between a number of potential defects in different genes, although at this level it is not looking at the phenotypic variation brought about by different mutations in the same gene. For single gene defects which have a large phenotypic variation or even manifest as two or more distinct diseases (and we will get into philosophical discussion if we try to define when a phenotypic variant become a different disease state) particularly if there is