Premarital Counseling on the Alpha Thalassemia Allele HBA2:c.*94A>G

Abstract

The mutation HBA2:c.*94A>G (AATAAA>AATAAG; rs63751269) is a 3′-UTR (3 prime untranslated region) single-nucleotide substitution in the polyadenylation (PA) signal of HBA2 (αPA:A→G). This pathogenic (CADD score, 14.92) variant is sporadic in the Arabian Peninsula. It results in inefficient mRNA processing, transcription termination, and possibly using an alternate cryptic downstream polyadenylation signal. As a result, the allele αT (or αT-Saudi) poses challenges in premarital counseling with respect to fetal risk of hemoglobin H disease. Homozygous HBA2:c.*94A>G (αTα/αTα) results in moderate-to-severe microcytosis (mean red cell volume, MCV, 55 to 65 fL), reflecting markedly impaired hemoglobin synthesis (hemoglobin H disease). Homozygous rightward −α3.7 (a 3804-neocleotide deletion allele, NM_000517.4:c.[-2_-3delAC; −α3.7]), on the other hand, results in mild microcytosis (MCV, 70 to 75 fL, alpha-thalassemia trait). Thus, HBA2:c.*94A>G is more damaging than −α3.7. Consistently, the value of MCV in compound heterozygosity, HBA2:c.*94A>G and −α3.7, is 65 to 70 fL. We report here a healthy couple who presented for premarital counseling on their hemoglobinopathy. The man has homozygous HBA2:c.*94A>G (αTα/αTα), and the woman has compound heterozygous (−α3.7/αTα, also annotated as: −3.7α/αTα). As a result, the genotype of their offspring would be that of the father (αTα/αTα) or the mother (−α3.7/αTα). The counseling was mainly based on the benign phenotypes of the parents. As both were asymptomatic and their anemia was clinically insignificant, they proceeded with the marriage.