Thalassemias; genotype/phenotype correlation; molecular heterogeneity . dependent thalassemia major to the mild form of thalassemia intermedia . Genotype-phenotype correlation among beta-thalassemia and including mild beta-thalassemia intermedia (TI) and severe beta-thalassemia. gotes with a thalassemia intermedia phenotype the modifying factor has not been partially elucidated the relationship between genotype and phenotype.
This is combined with increased iron from the breakdown of RBCs and the increased iron introduced into the circulation by the transfusions necessary to treat thalassemia, plus inadequate excretory pathways lead to progressive deposition of iron in tissues and hemosiderosis occurs [ 13 ]. These free iron species generate reactive oxygen species with eventual tissue damage, organ dysfunction, and death Figure 1 [ 13 ].
History The history in patients with thalassemia widely varies, depending on the severity of the condition and the age at the time of diagnosis.
Beta-thalassemia: from genotype to phenotype
Some patients, especially those with somewhat more severe forms of the disease, manifest some pallor and slight icteric discoloration of the sclerae with splenomegaly, leading to slight enlargement of the abdomen.
Thalassemia should be considered in any child with hypochromic microcytic anemia that does not respond to iron supplementation [ 15 ]. Physical Patients with thalassemia minor are often asymptomatic. Diabetes and thyroid or adrenal disorders have been described in these patients [ 16 ]. Platelet count is usually normal, unless the spleen is markedly enlarged. Peripheral blood film examination reveals nucleated RBCs and occasional immature leukocytes. Hemoglobin electrophoresis High performance liquid chromatography HPLC is now usually used as first-line method to diagnose hemoglobin disorders.
HPLC or hemoglobin electrophoresis reveals absence or almost complete absence of Hb A, with almost all the circulating hemoglobin being Hb F. The Hb A2 percentage is normal, low, or slightly raised. Biochemical studies Serum iron and ferritin: Serum iron level and ferritin levels are elevated.
However, an assessment using serum ferritin levels may underestimate the iron concentration in the liver. Transferrin saturation is a surrogate marker for NTBI [ 17 ]. Hepcidin can be measured in serum and urine using mass spectrometry, and this may be a feasible marker in the near future [ 19 ]. Serum zinc, serum and leucocytic ascorbic acid, vitamin E, and folic acid are low.
LDL is elevated as consequence of ineffective erythropoiesis [ 20 ]. Imaging studies Findings show skeletal changes, including thinning of the cortex, widening of the medulla, and coarsening of trabeculations, due to bone marrow hyperplasia in the long bones, metacarpals, and metatarsals.
These changes contribute to the classic chipmunk facies observed in patients with thalassemia major [ 21 ]. Chest radiography is used to evaluate cardiac size and shape. This procedure has shown decreased values in cardiac T2 due to iron deposit in the heart. Unlike liver MRI, CMR does not correlate well with the ferritin level, the liver iron level, or echocardiography findings. The liver is clear of iron loading much earlier than the heart, and so the decision to stop or reduce chelation treatment based on liver iron levels is misleading [ 23 ].
- Relationship between genotype and phenotype. Thalassemia intermedia.
- Thalassemia — From Genotype to Phenotype
The molecular basis of the thalassemias has been scrupulously expounded and represents one of the first diseases to be characterized at the molecular level. Different mutations; point mutations, small insertions, deletions, or, in some cases, partial or large deletions encompassing one or two globin genes alter the function of the genes encoding a globin chain [ 31 ].
Genotype-phenotype correlation among beta-thalassemia and beta-thalass | JBM
However, they were reported in some regions with high consanguinity rates such as in Saudi Arabia and the surrounding Gulf countries [ 31 ]. These regions are divided into homologous sub-segments X, Y, and Z. Another common crossover between homologous X boxes, which are 4. Further recombination events could give rise to other unusual rearrangements. The extent of the deletion is shown as bars, and thin lines indicate regions of uncertainty of the breakpoints  Figure 7.
These new observations may increase the understanding of normal control of globin gene expression, as well as clarify common genetic or epigenetic mutations that contribute to the development or progression of myelodysplasia [ 5 ]. Schematic representation of the spectrum of ATRX mutations. One normally functioning beta gene, even if the other one produces no beta chain, would clinically present itself as mild anemia [ 37 ] that would be detected during a routine laboratory blood evaluation.
The severity of the disorder depends in part on the combination of genes that have been inherited: More than disease-causing mutations have been identified so far.Genotypes, Phenotypes and Punnett Square
While most alleles behave as Mendelian recessives, there are variants that cause a disease phenotype even when present in a single copy. Beta globin gene mutations  Most of reported beta globin gene mutations are single nucleotide substitutions or deletions or insertions Fig. Gross gene deletion beta- thalassemias were reported in rare conditions.
A complete updated list of beta-thalassemia mutations is available through the Globin Gene Server website [ 40 ]. In exons 1 or 2 mutations, a very small amount of beta globin mRNA is found in the cytoplasm of red blood cell precursors, whereas exon 3 mutations are associated with a substantial amount of abnormal cytoplasmic mRNA. On the other hand, exons 1 and 2 premature termination codon mutations activate nonsense-mediated mRNA decay, thus precluding the accumulation of mRNA encoding for truncated peptides [ 4142 ].
Whereas, mutations in exon or intron sequences may activate a cryptic splicing site leading to abnormal mRNA processing with defective splicing at variable degrees, and consequential mild to severe phenotypic affection [ 4142 ].
Another group of splicing mutations involve nucleotide replacements within introns that create a new splice site that is used preferentially to the normal site.
New splice sites may also be created by nucleotide substitutions in exons. These may also produce an amino acid change that would then produce an abnormal globin chain, leading to the production of reduced protein amounts.
Beta-thalassemia: from genotype to phenotype
Mutations affecting RNA stability: Downstream AUG sequences are not matched to the consensus sequence for translation initiation and would result in a shifted reading frame and a premature stop codon [ 44 ]. Different polymorphisms at the BCL11A gene on 2p Also, while it is likely that future studies will better define the genetic polymorphisms that modulate the effect of the BCL11A and HBS1L-MYB intergenic region loci and eventually uncover causal variants, results from Badens et al.
Furthermore, future studies will probably expand this predictive ability, including the effect of the different strongest independent predictors known to date for each gene or even identified causal variantsand will eventually relate genetic modifiers to a more detailed measurement of clinical severity. Linkage analysis and genome-wide association studies have greatly contributed to such results, and next generation sequencing might further improve prediction ability and eventually guide the development of new therapies.
β-Thalassemia: Genotypes and Phenotypes
At present, recent studies on Hb F modifier genes have produced mixed results: Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine.
Blackwell Science Ltd; Genotype-phenotype correlations in beta-thalassemias. Galanello R, Cao A. Relationship between genotype and phenotype. Ann N Y Acad Sci. Molecular basis of delta beta-thalassemia with normal fetal hemoglobin level. Blood Cells Mol Dis.