A pregnant woman seeking prenatal diagnosis of beta thalassemia demonstrated the following test results:
Hemoglobin electrophoresis:
Hb A1 92.3%
Hb A2 7.7%
CBC:
Hb 11.8 g/dL
MCH 20 pg
MCV 63.6 fL
RBC 5.91 million/uL
However, when beta globin gene was sequenced, no mutations were found. The sequence information obtained covered two regions:
1. from the upstream nucleotide -101 to the nucleotide 35 of intron 2
2. from the nucleotide 556 of intron 2 till the end of 3' UTR
Only homozygous polymorphisms such as CD-2 C>T, IVS II-16 C>G, and IVS II-666 T>C were found. A definite answer is needed for genetic counseling. Any advice will be very much appreciated. Thank you.
Very high levels of A2 (>6%) have been reported in beta-thalassemia caused by gene deletions rather than the more usual base substitutions, which would be why you had no detectable mutations by sequencing and had homozygous polymorphisms. You could try to confirm with a copy number variation assay rather than sequencing. Best approach might be to counsel mom as though she had beta-thalassemia trait, and probably beta(0)thalassemia trait at that.
since you have hignt level of Hb A2 and only homozygous polymorphisms by DNA sequencing,this indicates,most likely a beta gene l deletion and no simple mutation. It could be of interst to analyse the parents of the proband for the cited polymorphisme.The genotypes of both parents for these SNP could clarify the situation for wether there is a deletion or no. Otherwise MLPA protocol will be necessary to confirm the b gene deletion.
Patient DNA should be tested for deletion/duplication by MLPA for example. Most importantly what is the status of her partner?
The partner is diagnosed with beta thalassemia trait. A heterozygous point mutation has already been detected.
If one child of the offspring of this couple presents a major b thalassemia and homozygote for trhe father's mutation, this will be a good argument for the presence of heterozygote b gene deletion in the mother.
If there is a deletion within the beta-gamma cluster an old-fashioned Southern blot might answer the question
check using MLPA but the great difference is the partner's HPLC for the future of the newborn.
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