Beta‐thalassaemia intermedia: is it possible consistently to predict phenotype from genotype?

Eighty‐seven patients with β thalassaemia of intermediate severity were investigated in our Unit to determine whether it is possible to consistently predict phenotypic severity from genotypic factors. The subjects were from the following ethnic backgrounds: Asian Indian (35.1%), Middle Eastern (24.3%), Mediterranean (21.6%), Northern European (14.9%) and South‐East Asian/Chinese (4.1%). There was a wide spectrum of phenotypic severity; 49 had mild disease, 22 moderate and 16 severe disease. 22/87 patients had inherited only a single copy of a β‐thalassaemia allele, of whom 11 had also co‐inherited triplicated α genes (ααα/αα or ααα/ααα) and seven had dominantly inherited β thalassaemia. In four of the heterozygotes no explanation was found for the thalassaemia‐intermedia phenotype. 65/87 patients were homozygous or compound heterozygous for 26 mutations (40 genotypes) which ranged from very mild β+ to β° thalassaemia alleles. All patients with two mild or very mild β+ thalassaemia alleles had mild to moderate disease. Although concurrent inheritance of extra α genes with heterozygous β thalassaemia results in thalassaemia intermedia, the disease is mild. Co‐inheritance of α thalassaemia as a modulating factor was not evident in this cohort of patients. Presence of the in‐cis Xmn I‐Gγ site was a modulating factor but insufficient to explain the high fetal haemoglobin levels encountered. In conclusion, apart from the two categories of triplicated α genes with heterozygous β thalassaemia and inheritance of mild β+ thalassaemia alleles, it was not possible to consistently predict phenotype from α and β genotypes alone, due to the influence of modulating factors, some implicated (such as inheritance of HPFH determinants) and others as yet unidentified.

[1]  ScienceDirect.  Baillière's clinical haematology , 1998 .

[2]  A. Oppenheim,et al.  Genetic analysis of β‐thalassemia intermedia in Israel: Diversity of mechanisms and unpredictability of phenotype , 1997, American journal of hematology.

[3]  S. Thein,et al.  Moderate reduction of beta-globin gene transcript by a novel mutation in the 5' untranslated region: a study of its interaction with other genotypes in two families. , 1996, Blood.

[4]  C. Buswell.  Beta thalassaemia. , 1996, Professional nurse.

[5]  G. Lathrop,et al.  Dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach , 1996, Nature Genetics.

[6]  E. Baysal,et al.  The β- and δ-Thalassemia Repository (Eighth Edition) , 1995 .

[7]  M. Cappellini,et al.  Genetic interactions in thalassemia intermedia: Analysis of β‐Mutations, α‐Genotype, γ‐Promoters, and β‐LCR hypersensitive sites 2 and 4 in Italian patients , 1995 .

[8]  S. Thein,et al.  Immunochemical estimation of haemoglobin types in red blood cells by FACS analysis , 1994, British journal of haematology.

[9]  A. Oppenheim,et al.  Severe thalassaemia intermedia caused by interaction of homozygosity for α‐globin gene triplication with heterozygosity for β thalassaemia , 1994 .

[10]  G. Lathrop,et al.  Detection of a major gene for heterocellular hereditary persistence of fetal hemoglobin after accounting for genetic modifiers. , 1994, American journal of human genetics.

[11]  S. Thein,et al.  Beta-thalassemia unlinked to the beta-globin gene in an English family. , 1993, Blood.

[12]  R. Barnetson,et al.  The molecular basis of HPFH in a British family identified by heteroduplex formation , 1993, British journal of haematology.

[13]  K. Davies.  Human genetic disease analysis: a practical approach , 1993 .

[14]  R. Barnetson,et al.  Beta thalassaemia in the indigenous British population , 1992, British journal of haematology.

[15]  G. Loudianos,et al.  A β‐thalassaemia phenotype not linked to the β‐globin cluster in an Italian family , 1992 .

[16]  A. Cao,et al.  Promoter mutations producing mild β‐thalassaemia in the Italian population , 1992, British journal of haematology.

[17]  M. Vidaud,et al.  A comprehensive scanning method for rapid detection of β‐globin gene mutations and polymorphisms , 1992, Human mutation.

[18]  S. Thein,et al.  A NOVEL MUTATION (NONSENSE β 127) IN EXON 3 OF THE β GLOBIN GENE PRODUCES A VARIABLE THALASSAEMIC PHENOTYPE , 1991 .

[19]  S. Thein,et al.  A simple and rapid method of direct sequencing using Dynabeads , 1991, British journal of haematology.

[20]  A. Hoffbrand,et al.  A novel δº mutation in cis with Hb Knossos: a study of different genetic interactions in three Egyptian families , 1991 .

[21]  S. Thein,et al.  Hemoglobin Chesterfield (beta 28 Leu----Arg) produces the phenotype of inclusion body beta thalassemia [letter] , 1991 .

[22]  D. Weatherall,et al.  Rapid detection and prenatal diagnosis of β-thalassaemia: studies in Indian and Cypriot populations in the UK , 1990, The Lancet.

[23]  J. Clegg,et al.  Molecular basis for dominantly inherited inclusion body beta-thalassemia. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[24]  G. Loudianos,et al.  The C–T substitution in the distal CACCC box of the β‐globin gene promoter is a common cause of silent β thalassaemia in the Italian population , 1990 .

[25]  R. Galanello,et al.  Molecular analysis of beta zero-thalassemia intermedia in Sardinia. , 1989, Blood.

[26]  A. Kutlar,et al.  Molecular characterization of β‐globin gene mutations in Malay patients with Hb E‐β‐thalassaemia and thalassaemia major , 1989 .

[27]  S. Orkin,et al.  Beta-thalassemia due to two novel nucleotide substitutions in consensus acceptor splice sequences of the beta-globin gene. , 1989, Blood.

[28]  D. Weatherall,et al.  The molecular basis of thalassaemia major and thalassaemia intermedia in Asian Indians: application to prenatal diagnosis , 1988, British journal of haematology.

[29]  A. Kutlar,et al.  Mild and severe beta-thalassemia among homozygotes from Turkey: identification of the types by hybridization of amplified DNA with synthetic probes. , 1988, Blood.

[30]  G. Saglio,et al.  A benign form of thalassaemia intermedia may be determined by the interaction of triplicated α locus and heterozygous β‐thalassaemia , 1987 .

[31]  J. Wainscoat,et al.  Thalassaemia intermedia: interaction of the triple α‐globin gene arrangement and heterozygous β‐thalassaemia , 1987 .

[32]  Y. Kan,et al.  The molecular basis of beta-thalassemia in Lebanon: application to prenatal diagnosis. , 1987, Blood.

[33]  D. Weatherall,et al.  Association of thalassaemia intermedia with a beta‐globin gene haplotype , 1987, British journal of haematology.

[34]  Henry A. Erlich,et al.  Characterization of β-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA , 1987, Nature.

[35]  J. Delaunay,et al.  Homozygous hemoglobin Knossos (alpha 2 beta 227(B9) Ala----Ser): a new variety of beta+-thalassemia intermedia associated with delta degree- thalassemia , 1986 .

[36]  T. Huisman,et al.  DNA sequence variation associated with elevated fetal G gamma globin production. , 1985, Blood.

[37]  D. Labie,et al.  Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[39]  W. Wood,et al.  β + Thalassaemia—Portuguese type: clinical, haematological and molecular studies of a newly defined form of β thalassaemia , 1983 .

[40]  R. Taramelli,et al.  A gene controlling fetal hemoglobin expression in adults is not linked to the non‐alpha globin cluster. , 1983, The EMBO journal.

[41]  J. Clegg,et al.  Thalassaemia intermedia in Cyprus: the interaction of alpha and beta thalassaemia. , 1983 .

[42]  J. Clegg,et al.  Thalassaemia intermedia in Cyprus: the interaction of α and β thalassaemia , 1983, British journal of haematology.

[43]  S. Orkin,et al.  Linkage of β-thalassaemia mutations and β-globin gene polymorphisms with DNA polymorphisms in human β-globin gene cluster , 1982, Nature.

[44]  J. Clegg,et al.  Separation of the α and β-Chains of Human Haemoglobin , 1968, Nature.

[45]  J. Clegg,et al.  Separation of the alpha and beta-chains of human hemoglobin. , 1968, Nature.