A marked genetic and clinical variability of the Hb H syndrome occurs because of the molecular heterogeneity of alpha-thalassemia (thal). The hallmark is the presence of excess beta chains forming Hb H (beta tetramer). In the Chinese, classical Hb H disease presents as "alpha-thalassemia intermedia" and is due to a double heterozygosity for two deletional forms of alpha-thal, alpha-thal-1 and alpha-thal-2. The majority of cases with an alpha-thal-1 defect have a deletion of at least 18.1 kb starting 3' to the zeta 1 gene which includes the psi alpha and the two alpha genes; it is similar to that described in Thais. However, two families had a deletion of the entire zeta-alpha gene cluster, i.e. zeta-alpha-thal-1. Of 33 alpha-thal-2 defects studied, 26 were the rightward deletion (alpha -3.7 kb, all type I defects) and seven the leftward deletion (alpha -4.2 kb); one of the latter was associated with Hb Q. About 10% of the alpha-thal defects belong to the nondeletion type, the most common form being Hb Constant Spring (CS). This anomaly, when coinherited with alpha-thal-1, produces Hb H-CS disease which has a most marked anemia and splenomegaly due to the instability of the alpha-CS chain. Hb Quong Sze produces an alpha-thal-2 because of the unstable alpha-Quong Sze chain. One patient who inherited classical Hb H disease and Hb New York (NY) [alpha 113(G15)Val----Glu] had severe anemia, and required frequent blood transfusions due to the deleterious effect of an increased alpha-NY chain turnover.(ABSTRACT TRUNCATED AT 250 WORDS)