Answering your question(s) is not an easy task. You are right there are two types of classification of the beta-thalassemias. The 1rst one is based on the consequence of the mutation. I would call them mutations rather than SNPs i. because single nt changes are just one type of b-thal defects, some are deletions or insertions, ii. because SNPs are by definition present in a given population at a frequency higher 1%, and iii. because SNPs are most often silent polymorphisms (although not always). Indeed mutations responsible for the total absence of production of beta-globin chains are classified as beta0-thal, whereas mutations that result only in a decreased production are classified as beta+-thal mutations. The second classification is clinical: beta-thal major is a life-threatening transfusion-dependent condition, whereas beta-thal intermedia patients are not transfusion dependent. The problem is that, even though some beta-thal mutations are clearly severe and other mild, or even silent, in many cases there is no direct relationship between the beta0/beta+ nature of the mutation and its clinical consequences. This is first because the beta+ mutations vary very much in terms of residual quantity of beta-chain produced, second because there is a compensatory production of fetal Hb that varies very much from one individual to an other that may be linked to the beta-globin gene cluster but also to independent loci (on chromosomes 2 and 6 for instance).

You are mentioning that “more 20 SNPs” can give rise to beat-thalassemia, actually the number of documented beta-thal mutations to date is higher than 250 (for details see the HbVar Hb variant data base http://globin.bx.psu.edu/hbvar). You may find additional insights in the superb review “Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias” by Sir David J. Weatherall (Nat Rev Genet. 2001, 4:245-55)

Thanks Jacques,

Your answer made it clear that the clinical manifestations may vary in individuals due to unknown factors. It is pretty much clear to me. But now I am more focussed on the genetics of the danger mutations. Let me present my questions in more technical way.

Suppose I have a patient thal-minor husband with HBB:c92+5 G>C heterozygous mutation and wild type locus for HBB:c 47G>A and his wife with HBB:c 47G>A heterozygous mutation and wild type HBB:c92+5 G>C locus. First one is Beta+ mutation and second one is beta-0 mutation. HPLC analysis of their samples with term them as Thal-minor and doctor will ask them not to concieve a child. Doctor will not go to the extent of analzing the genetics. Now my question arises. I am talking about the 75% chances where the child is carrier or major and not 25% normal. If they concieve, theoritically the child will not be Homozygous for either of the mutations. Now as in genetics we can not call the child "thal-major" unless any mutation is present in homozygous. But clinically we can get a " thal-major" child with 25 chances for this couple although genetics doesnt seem to answer the question.

The 20 mutations I have mentioned earlier has been taken from HbVar databse only. But i sorted them for their availablity in India. So may there are more than 250 mutations but only 20 someting significant nationwide in India.

May be I am asking a not viable question as I have not yet heard of such a genetic case in literature. But if it is possible then what?

Beta Thalassemia major is caused by homozygous or compound heterozygous mutations in beta - globin gene. First of all, we must clear the confusion of SNP or mutation. SNP or single-nucleotide-polymorphisms are 'normal' variations in our genome and some of them happen to fall within a gene. When a single nucleotide variation leads to altered function of the gene - then it becomes a mutation. For two individuals (Couple) harboring pathogenic mutations in heterozygous state (meaning that they are carriers) - their offspring would have a 25% chance of receiving 'both' the pathogenic mutations from parents - and thus leading to major thalassemia - either in homozygous state (if parents are carrying the same mutation) or compound heterozygous state (wherein parents are carrying different mutations). The classification of beta-plus and beta-zero - is dependent on the type of 'mutation' - both these types have to have a mutation and not a SNP. When there is a mild mutation - which means that beta globin is still being synthesised or has some residual function - then the person will have beta plus,.

I hope this makes things clear for you. cheers!

Thanks Sunita Ji,

Your use of the terminology " compund heterozygous" has made the things clear to me. I do understand the difference between SNP and mutation but i it seems my question here may have been put wrong with use of SNP in place of mutations.

Thanks for the explanation and now I think with these two answers I can do my analysis correctly.

Thanks