ClinVar Genomic variation as it relates to human health

Langdown et al. (1989) described a doubly substituted sickling hemoglobin with the change of glu-to-val at beta 6 (141900.0243) and glu-to-lys at beta 121 (141900.0202). The double substitution resulted in a variant with reduced solubility and apparent increase in red cell sickling tendency. Hemoglobin S (Oman) combines the classic Hb S mutation (glu6 to val), with the Hb O (Arab) mutation (glu121 to lys). Nagel et al. (1998) studied a pedigree of heterozygous carriers of Hb S (Oman) that segregated into 2 types of patients: those expressing about 20% Hb S (Oman) and concomitant -alpha/alpha-alpha thalassemia and those with about 14% of Hb S (Oman) and concomitant -alpha/-alpha thalassemia. The higher expressors of Hb S (Oman) had a sickle cell anemia clinical syndrome of moderate intensity, whereas the lower expressors had no clinical syndrome and were comparable to the solitary case first described in Oman. In addition, the higher expressors exhibited a unique form of irreversibly sickled cell reminiscent of a 'yarn and knitting needle' shape, in addition to folded and target cells. Purified Hb S (Oman) has a C(SAT) (solubility of the deoxy polymer) of 11 g/dL, much lower than Hb S alone (17.8 g/dL). Another double mutant, Hb S (Antilles) (141900.0244), has a similarly low C(SAT) and much higher expression (40 to 50%) in the trait form, but has a phenotype that is similar in intensity to the trait form of Hb S (Oman). Nagel et al. (1998) concluded that the pathology of heterozygous S (Oman) is the product of recipient properties of the classic mutation which are enhanced by the second mutation at beta-121. In addition, the syndrome is further enhanced by a hemolytic anemia induced by the beta-121 mutation. They speculated that the hemolytic anemia results from the abnormal association of the highly positively charged Hb S (Oman) (3 charges different from normal hemoglobin) with the RBC membrane. To characterize better the clinical and laboratory aspects of Hb S (Oman), also called Hb S/O (Arab), Zimmerman et al. (1999) reviewed the Duke University Medical Center experience. They identified 13 African American children and adults with Hb S/O (Arab), ranging in age from 2.7 to 62.5 years. All patients had hemolytic anemia with a median hemoglobin of 8.7 gm/dL and a median reticulocyte count of 5.8%. The peripheral blood smear typically showed sickled erythrocytes, target cells, polychromasia, and nucleated red blood cells. All 13 patients had had significant clinical sickling events, including acute chest syndrome (11), recurrent vasoocclusive painful events (10), dactylitis (7), gallstones (5), nephropathy (4), aplastic crises (2), avascular necrosis (2), leg ulcers (2), cerebrovascular accident (1), osteomyelitis (1), and retinopathy (1). Death had occurred in 4 patients, including 2 from pneumococcal sepsis/meningitis at ages 5 and 10 years, 1 of acute chest syndrome at age 14 years, and 1 of multiorgan failure at age 35 years. Zimmerman et al. (1999) concluded that Hb S/O (Arab) disease is a severe sickling hemoglobinopathy with laboratory and clinical manifestations similar to those of homozygous sickle cell anemia. (less)