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Two Chinese patients with mild and moderate Hb H disease were investigated for rare mutations on the α-globin genes (HBA1, HBA2) in addition to the - -(SEA) deletion. One patient was a 41-year old man with mild anemia (Hb 11.3 g/dL). Multiplex ligation-dependent probe amplification (MLPA) revealed a rare 2392 bp deletion involving the entire HBA1 gene. Mapping by gap-polymerase chain reaction (gap-PCR) defined the exact breakpoints of this deletion (HBA1: g36859_39252del2392) and confirmed its identity with a recently reported HBA1 deletion found in a Southern Chinese. The other patient was a 53-year old man with moderate anemia (Hb 9.5 g/dL). Automated direct nucleotide (nt) sequencing identified a novel single nt deletion at codon 40 (HBA2: c.123delG). This leads to a frameshift that modifies the C-terminal sequence to (40)Lys-Pro-Thr-Ser-Arg-Thr-Ser-Thr(47)COOH and the introduction of a stop codon TGA 23 nts downstream. These two cases demonstrate the power of MLPA and direct nt sequencing to detect and characterize rare and novel mutations. They also highlight the differential effect of HBA1 and HBA2 gene mutations on an α-thalassemia (α-thal) phenotype due to their different transcriptional activity.

An extended family with three individuals affected by two different forms of double heterozygosity for beta-thalassemia and Hb New York is reported. Double heterozygosity of Hb New York [beta 113 GTG-->GAG; VAL-->GLU] and beta degrees codon 17 was detected in a fetus following prenatal screening for thalassemia. The father and a paternal aunt were also found to be heterozygous for Hb New York and beta degrees IVSII-654. Both adults had clinical and hematological features consistent with beta-thalassemia trait. The affected child was followed up after birth and manifested the typical course of a thalassemia trait, with no signs of organomegaly or overt hemolysis. Observations strongly suggest that double heterozygosity of Hb New York and beta degrees thalassemia has mild, if any, clinical symptoms, and is not an indication of therapeutic abortion when detected antenatally.

We report the first case of Hb Phnom Penh where a molecular study was done on the patient's sample. The result confirmed the predicted DNA sequence change involved in the mutation, which was delineated by another group in 1998 using amino acid analysis.

There have been two previous reports on Hb Val de Marne (Hb Footscray) [alpha133(H16)Ser-->Arg] in the literature, but the molecular characterization has hitherto not been described. Based on the Ser-->Arg transition, the presumed mutation was cited as AGC-->CGC of the alpha2- or alpha1-globin gene. We have found this variant in a 15-year-old Chinese girl and her father, and automated DNA sequencing revealed an AGC-->AGA mutation at codon 133 of the alpha2-globin gene. Since an increasing number of alpha-globin gene variants have been reported with the same protein alteration but with different mutations on the alpha1- or alpha2-globin genes, the mutation identified in the present family does not preclude the presence of other alpha-globin gene mutations leading to this hemoglobin (Hb) variant.

Two brothers from a Chinese family with beta-thalassemia intermedia who harbor both alpha- and beta-globin gene defects are described. They are both compound heterozygous for codons 41/42 (-CTTT) beta0-thalassemia and nt - 28 (A > G) beta(+)-thalassemia mutations together with concurrent (- -SEA) alpha-thalassemia (SEA) deletion. One sibling also harbors Hb Westmead, giving an unusual genotype of beta0/beta(+)-thalassemia and (- -SEA) alpha-thalassemia/Hb Westmead. With respect to the age at presentation and transfusion requirement, this subject shows a milder clinical phenotype than his brother, most probably explainable by the presence of Hb Westmead in addition to the SEA deletion, which causes a further amelioration of the alpha-chain excess and hence a less severe disease. For areas with high prevalence of both alpha- and beta-thalassemia mutations, their interactions should always be considered in genotype phenotype correlation. Moreover, routine laboratory diagnostic strategy for non-deletional alpha-globin gene mutations in the Chinese may need to include Hb Westmead, as it is a common alpha-globin gene mutation in our population apart from Hb Constant Spring and Hb Quong Sze.