A Paradigm shift in genotype‐phenotype relationships in β‐thalassaemia

The ability to predict the severity of any disease from the time of diagnosis is very valuable for the follow-up of individuals with the disease. Monogenic diseases, such as those that involve haemoglobin, were among the first diseases for which genotype-phenotype relationships were described and confirmed, allowing the prediction of disease severity. Thalassaemia was found to be due to an imbalance of alpha and beta globin subunit synthesis. Even before the identification of mutations, the biological variability could be measured using globin chain synthesis ratios, which were used for predicting a patient’s long-term prognosis. The small size of the globin genes (around 2 kb) facilitates their cloning and sequencing. Point mutations were first identified in the human b-globin gene over 40 years ago. The discovery of polymerase chain reaction testing accelerated the detection of the several hundred mutations that impair production of b-globin chains by varying degrees, causing a disease of varying severity. Mutations are termed b, if the mutation completely abolishes b-globin synthesis from that gene; b, for partial reduction in b-globin production; and b, for very mild mutations that only minimally reduce globin output. Patients can be homozygous or compound heterozygous for any of these mutations, thus many genotypes exist with highly variable degrees of severity. For decades, the identification of each patient’s mutations has been critical for prenatal diagnosis, carrier screening and genetic counseling. More recently, the prediction of disease severity based on genotype has been used as a criterion for referral for patients for novel therapies such as gene therapy. Musallam et al have performed the largest (˃2 100 patients) and most geographically varied, long-term followup of b-thalassaemia patients studied contemporaneously. The patients are from the USA, Europe, the Middle East and North Africa (the latter two being combined for some analyses and termed MENA). Most of the patients were born after 1970, but 15% (325 patients) were born before that time. Using five different models of comparison, the authors conclude that there is little difference in the long-term outcome (mortality and comorbidities) between patients with any of the genotypes (b and b), apart from patients with the mildest genotypes (carrying at least one b mutation). This is a bewildering, and rather discouraging, conclusion for the many who have toiled in the laboratory to determine the precise genetic aetiology of b-thalassaemia. Virtually the same group of authors has previously described a “complication risk score” (CoRS) that categorized the phenotypic severity of b-thalassaemia into low, intermediate, high and very high-risk phenotypes. That study included 7 910 patients and the genotypic analysis presented in their current study was performed on a subset of those patients. The genotypic severity, as defined in the present study, was found to have no correlation with the previously designated CoRS. The best predictors of disease severity in the CoRS study were age, whether or not the patient was receiving transfusions and indices of iron overload, such as cardiac ejection fraction. While the results presented by Musallam et al. seem to challenge the significance of the genotype-phenotype relationship, which has long been crucial for clinicians and geneticists, this study suggests that there is in fact a genotype-phenotype relationship, but the clinical picture of b-thalassaemia is changing. At the present time, the disease can be viewed as corresponding to a binary genotypic classification, severe or mild, instead of the former gradual continuum of genotypic severity. The genotypically moderate and severe groups have similar clinical outcomes and only the mildest Correspondence: Deborah Rund, Hematology Department, Hebrew University Hadassah Medical Organization, Ein Kerem, Jerusalem, Israel 91120. E-mail: Deborah.rund@mail.huji. ac.il commentary