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Journal: Hemoglobin

27

Both α- and β-thalassemia (α- and β-thal) are highly prevalent in the population of the Al-Qatif and Al-Ahsa regions in the Eastern Province of Saudi Arabia. This study provides a more precise picture of the α-thal mutations prevalent in 104 transfusion-dependent β-thal patients in the Eastern Province. Detection of α-thal mutations was carried out using the α-globin StripAssay kit. A total of 12 α-thal mutations (21 genotypes) were identified in 33.7% of the chromosomes (46 patients). The heterozygous and homozygous -α(3.7) (α(+)) deletion mutations were the most prevalent in the β-thal patients (21.7%). We identified three α(0) deletions [- -(MED), - -(FIL) and -(α)20.5] that have not been previously reported for the population of Saudi Arabia. The seven point mutations identified in the β-thal patients were: codon 14 [TGG>TAG (α1)], codon 59 [GGC>GAC (α1)] (Hb Adana), polyadenylation signal site (polyA1) [AATAAA>AATAAG (α2)], codon 142 [TAA>TCA (α2)] (Hb Koya Dora), codon 59 [GGC>GAC (α2)] (Hb Adana), initiation codon [ATG>ACG (α2)] and the ααα(anti 3.7) gene triplication. The Hb Koya Dora mutation occurred at the highest frequency (15.38%). Comparison of the clinical phenotype of β-thal patients, with and without an α-thal mutation, showed that patients with β-thal alone had a significantly elevated level of alanine transaminase (ALT) (mean 72.5 IU/L) and aspartate transaminase (AST) (mean 71.8 IU/L) (p <0.005). In addition, the β-thal patients without an α-thal mutation had a higher percentage of osteoporosis (16.6%), fractures (12.5%), and splenectomies (58.3%). This confirms previous data that the co-inheritance of α-thal in β-thal patients results in the amelioration of the clinical phenotype of β-thal patients. Moreover, the high frequency of α- and β-thal in the Eastern Province of Saudi Arabia and their coinheritance, necessitates the inclusion of α-thal testing in the current pre marital testing program to highlight the risk to the offspring of affected individuals.

Concepts: DNA, Gene, Aspartate transaminase, Alanine transaminase, Saudi Arabia, Eastern Province, Saudi Arabia, Al-Hasa, Dammam

25

We present the first description of a Chinese family with a β-thalassemia (β-thal) mutation -86 (C > G) (HBB: c.-136C > G). This mutation changes the conserved promoter sequence within the proximal CACCC box of the β-globin gene that leads to a phenotype of β(+)-thal. The β-globin haplotype analysis revealed that the -86 mutation in our case was linked with haplotype I [+ - - - - + +]. This haplotype was commonly found both in the β-thal mutation and the β(A) gene. Our results suggest that the -86 mutation possibly does not have a distinct origin.

Concepts: DNA, Gene, Cancer, Natural selection, Promoter, Evolution, DNA repair, Point mutation

25

Methemoglobinemia can be acquired (oxidizing drugs or chemicals products) or inherited either by mutations affecting globin chains [M hemoglobins (M Hbs)] or by defects in the enzymatic system involved in the reduction of spontaneous Hb oxidation: nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase. It is encoded by the CYB5R3 gene: there are two phenotypes of autosomal recessive congenital methemoglobinemia, in type II CYB5R deficiency is generalized and affects all cells, leading to an early onset, whereas in type I, the enzyme deficiency is restricted to erythrocytes, usually discovered in infancy but not exclusively. We report a new case of methemoglobinemia discovered in a patient from Bahrain who exhibited an unknown dyspnea at the age of 37 years without trigger events or oxidizing products. We discovered a new mutation in the CYB5R3 gene: exon 9, codon 266 (delGAG) (GLU) (CYB5R3: c.726_729delGAG) in the homozygous state. Appearance of methemoglobinemia in an adult usually suggests an acquired cause but our case illustrated that it could also reveal a type I mutation of cytochrome b5 reductase.

Concepts: DNA, Carbon dioxide, Evolution, Adenosine triphosphate, Enzyme, RNA, Redox, Nicotinamide adenine dinucleotide

25

The abnormal hemoglobin (Hb) with an aspartic acid to asparagine substitution at α64 has been found on both the α2- and α1-globin genes. It has been described in many different populations under different names, but never in Bulgaria. Using the recently proposed nomenclature, Hb G-Waimanalo [A1] refers to the HBA1: c.193G > A, while Hb G-Waimanalo [A2] refers to the HBA2: c.193G > A mutation. Here, we present the first family from Bulgaria with Hb G-Waimanalo [A1].

Concepts: Family, Protein, Amino acid, Biology, Aspartic acid, Bulgaria, Republic of Macedonia, Plovdiv

25

α-Thalassemia (α-thal) is a common genetic disorder in Iran and many parts of the world. Genetic defects in the α-globin gene cluster can result in α-thal that may develop into a clinical phenotype varying from almost asymptomatic to a lethal hemolytic anemia. Loss of one functional α gene, indicated as heterozygous α(+)-thal, shows minor hematological abnormalities. Homozygosity for α(+)- or heterozygosity for α(0)-thal have more severe hematological abnormalities due to a markedly reduced α chain output. At the molecular level, the absence of three α-globin genes resulting from the compound heterozygous state for α(0)- and α(+)-thal, lead to Hb H disease. Here we present a 21 nucleotide (nt) duplication consisting of six amino acids and 3 bp of intronic sequence at the exon-intron boundary, in both the α-globin genes, detected by direct DNA sequencing. This duplication was identified in three patients originating from two different Iranian ethnic groups and one Arab during more than 12 years. The clinical presentation of these individuals varies widely from a mild asymptomatic anemia (heterozygote in α1-globin gene) to a severely anemic state, diagnosed as an Hb H individual requiring blood transfusion (duplication on the α2-globin gene in combination with the - -(MED) double α-globin gene deletion). The third individual, who was homozygous for this nt duplication on the α1-globin gene, showed severe hypochromic microcytic anemia and splenomegaly. In the last decade, numerous α-globin mutations have demonstrated the necessity of prenatal diagnosis (PND) for α-thal, and this study has contributed another mutation as important enough that needs to be considered.

Concepts: DNA, Gene, Genetics, Mutation, Red blood cell, Anemia, Hematology, Microcytic anemia

24

We here report an unusual case of Hb Bart’s (γ4) disease. Thalassemia screening of a couple showed that the wife was an α(0)-thalassemia (α(0)-thal) carrier and her husband’s mean corpuscular volume (MCV) was normal. Chorionic villus sampling (CVS) was performed at 13 weeks' gestation for positive Down syndrome screening and chromosomal study of the cultured CVS showed a normal karyotype. Ultrasound examination at 22 weeks' gestation showed fetal cardiomegaly and raised middle cerebral artery peak systolic velocity. Cordocentesis confirmed fetal anemia and showed Hb Bart’s disease. Multiplex gap-polymerase chain reaction (gap-PCR) for α-thal deletions on DNA extracted from the CVS showed the presence of a homozygous α(0)-thal - -(SEA) (Southeast Asian) deletion. The husband was found to be a carrier of the α(+)-thal -α(3.7) (rightward) deletion. Non paternity was excluded by fluorescent PCR using short tandem repeat (STR) markers on chromosomes 13, 18 and 21. A de novo terminal deletion of chromosome 16 was excluded by array comparative genomic hybridization (aCGH). Detection of uniparental disomy (UPD), using STR markers on chromosome 16 showed maternal uniparental isodisomy from 16pter to 16p13.2, and uniparental heterodisomy from 16p13.13 to 16qter.

Concepts: DNA, Chromosome, Cytogenetics, Chromosomes, Aneuploidy, Y chromosome, Short tandem repeat, Uniparental disomy

0

We report a novel mutation on the β-globin gene, Hb Hezhou [β64(E8)Gly→Ser; HBB: c.193G>A] that was detected in two unrelated Chinese individuals. Patient 1 also carried an α+-thalassemia (α+-thal) -α4.2 (leftward) deletion, but hematological analyses showed no clinical consequences. Patient 2 was heterozygous for Hb Hezhou. Hemoglobin (Hb) analysis was performed using capillary electrophoresis (CE) and high performance liquid chromatography (HPLC). The Hb variant remained undetected using HPLC, while an additional peak was detected by CE. The finding of Hb Hezhou indicates that the possibilities of rare Hb variants should be alerted in the thalassemia screening program and precisely diagnosed depending on the Hb separation technique used.

0

The β-thalassemias and sickle cell disorders pose a considerable health burden in India. Of the more than 10,000 annual births of children with a severe hemoglobinopathy, only around 10.0% are managed optimally. Thus, genetic counseling and prenatal diagnosis (PND) is a valid option for a large and diverse country. Our center was one of the first to initiate PND and we present our experience over 30 years to evaluate the impact of awareness in changing the trends of PND of hemoglobinopathies. Both second and first-trimester diagnoses were undertaken by fetoscopy/cordocentesis and globin biosynthesis/high-performance liquid chromatography (HPLC) analysis of fetal blood and chorionic villus sampling (CVS) and DNA analysis. Over 30 years, 3478 couples (first trimester: 2475; second trimester: 1003) from all over India were offered PND. The number of couples coming in the first trimester increased significantly over each decade and couples coming prospectively increased from 2.5 to 18.4%. A cost-effective stepwise approach was used for molecular analysis. Eight hundred and one fetuses (23.0%) were affected and all except three couples opted for termination of these pregnancies. Genetic counseling and PND is the only way to reduce the burden of disease. With awareness, there was a shift from second trimester to first trimester PND over each decade, with an increasing number of couples coming during the first pregnancy. There are only 15 to 20 centers in India offering PND. We have compared our study with other reports on PND from different regions in India.

0

β-Thalassemia major (β-TM) is a severe genetic hemoglobin (Hb) disorder with cardiovascular complications such as atherosclerosis due to transfusion-dependent iron overload. We aimed to determine the associated factors with surrogate markers of subclinical atherosclerosis in these patients. Sixty subjects with β-TM referred to the Thalassemia Clinic of the Iranian Blood Transfusion Organization (IBTO) were included in our study. The blood samples were collected for laboratory measurements. The carotid intima-media thickness (CIMT), was measured by ultrasonography, and ankle-brachial index (ABI) was calculated. The multivariate linear analysis was performed to determine the appropriate indicators of subclinical atherosclerosis in β-TM. There was no significant difference in baseline characteristics between the study groups. In multivariate linear analysis, age and systolic blood pressure (SBP) were negatively associated with inverse-transformed CIMT [unstandardized β coefficient (B): -0.024, 95% confidence interval (95% CI): -0.032- -0.010, p < 0.001; B: -0.009, 95% CI: -0.017- -0.001, p 0.031, respectively]. There was also a significant correlation between the serum level of high-density lipoprotein cholesterol (HDL-C) and insulin with higher ABI, after adjustment for confounding variables (B: 0.003; 95% CI: 0.000-0.005; p = 0.030, and B: 0.004, 95% CI: 0.000-0.009, p = 0.037, respectively). Our results show that advancing age and increased SBP, HDL-C and insulin, associated with higher CIMT or ABI, are appropriate indicators of subclinical atherosclerosis in β-TM patients.

0

α0-Thalassemia (α0-thal) Chiang Rai (- -CR; NC_000016.10: g.144215_188843del) was identified as a novel 44.6 kb deletional type of α-thalassemia (α-thal), removing all α-like globin genes. However, little is known about the deleterious effects of this genetic disorder, particularly when it is combined with other types of thalassemia. We performed molecular analysis of the - -CR deletion using gap-polymerase chain reaction (gap-PCR) in two independent families residing in Phayao and Chiang Mai, Thailand, with an unknown causative mutation for Hb Bart’s hydrops fetalis syndrome and Hb H disease. Five out of seven individuals were diagnosed to be heterozygous for the - -CR deletion. Of these, two also carried Hb H disease with compound heterozygosities for - -CR and -α3.7 (rightward) deletions. However, hematological parameters of the - -CR carriers displayed microcytic hypochromic anemia that is comparable to other α0-thal traits. Although the prevalence of - -CR has never been elucidated in a specific population, our study demonstrated that genotyping for - -CR might be considered as an additional investigation for unexplained Hb Bart’s hydrops fetal syndrome and Hb H disease.