Coinheritance of a Rare Nucleotide Substitution on the β-Globin Gene and Other Known Mutations in the Globin Clusters: Management in Genetic Counseling.
A large number of methods for DNA analysis are available to identify defects in globin genes associated with hemoglobin (Hb) disorders. In this study, we report a rare nucleotide (nt) substitution on the β-globin gene, nt 781 in the second intron [IVS-II-781 (C > G); HBB: c.316-70C > G], identified in four patients. This nt substitution was previously described only as a personal communication to the HbVar database and indicated as a β(0) or β(+) mutation. The purpose of this study was to evaluate the clinical implication of this nt change, particularly when coinherited with severe β-thalassemia (β-thal), in order to be able to conduct appropriate genetic counseling. Genetic studies were performed on two subjects, one carried Hb S [β6(A3)Glu→Val; HBB: c.20A > T], and the other carried IVS-I-110 (G > A) (HBB: c.93-21G > A). All these subjects showed this new β nt substitution in association with Hb A2' (or Hb B2) [δ16(A13)Gly→Arg; HBD: c.49G > C]. Another 16 samples, carrying the same δ variant as the probands, were processed by β-globin gene sequencing in order to better understand the correlation between this Hb variant and the rare nt substitution reported in this study. The present investigation emphasizes the importance of sharing the observed nt changes in the globin gene cluster, especially in the case of new or rare undefined mutations, in order to facilitate the determination of their phenotypic expression, the possible interactions with known molecular defects and to formulate appropriate genetic counseling for at-risk couples.
a Department of Hematology and Rare Diseases , Unit of Rare Diseases of Blood and Blood-Forming Organs, Villa Sofia-Cervello Hospital , Palermo , Italy and.|b Department of Hematology and Rare Diseases , Unit for Molecular Diagnosis of Rare Diseases, Regional Reference Laboratory for Screening and Prenatal Diagnosis of Hemoglobinopathies, Villa Sofia-Cervello Hospital , Palermo , Italy.
Margherita
M
Vinciguerra
a Department of Hematology and Rare Diseases , Unit of Rare Diseases of Blood and Blood-Forming Organs, Villa Sofia-Cervello Hospital , Palermo , Italy and.|b Department of Hematology and Rare Diseases , Unit for Molecular Diagnosis of Rare Diseases, Regional Reference Laboratory for Screening and Prenatal Diagnosis of Hemoglobinopathies, Villa Sofia-Cervello Hospital , Palermo , Italy.
Cristina
C
Passarello
a Department of Hematology and Rare Diseases , Unit of Rare Diseases of Blood and Blood-Forming Organs, Villa Sofia-Cervello Hospital , Palermo , Italy and.|b Department of Hematology and Rare Diseases , Unit for Molecular Diagnosis of Rare Diseases, Regional Reference Laboratory for Screening and Prenatal Diagnosis of Hemoglobinopathies, Villa Sofia-Cervello Hospital , Palermo , Italy.
Filippo
F
Leto
a Department of Hematology and Rare Diseases , Unit of Rare Diseases of Blood and Blood-Forming Organs, Villa Sofia-Cervello Hospital , Palermo , Italy and.|b Department of Hematology and Rare Diseases , Unit for Molecular Diagnosis of Rare Diseases, Regional Reference Laboratory for Screening and Prenatal Diagnosis of Hemoglobinopathies, Villa Sofia-Cervello Hospital , Palermo , Italy.
Anna
A
Crivello
a Department of Hematology and Rare Diseases , Unit of Rare Diseases of Blood and Blood-Forming Organs, Villa Sofia-Cervello Hospital , Palermo , Italy and.
Maria
M
Fustaneo
a Department of Hematology and Rare Diseases , Unit of Rare Diseases of Blood and Blood-Forming Organs, Villa Sofia-Cervello Hospital , Palermo , Italy and.|b Department of Hematology and Rare Diseases , Unit for Molecular Diagnosis of Rare Diseases, Regional Reference Laboratory for Screening and Prenatal Diagnosis of Hemoglobinopathies, Villa Sofia-Cervello Hospital , Palermo , Italy.
Filippo
F
Cassarà
a Department of Hematology and Rare Diseases , Unit of Rare Diseases of Blood and Blood-Forming Organs, Villa Sofia-Cervello Hospital , Palermo , Italy and.|b Department of Hematology and Rare Diseases , Unit for Molecular Diagnosis of Rare Diseases, Regional Reference Laboratory for Screening and Prenatal Diagnosis of Hemoglobinopathies, Villa Sofia-Cervello Hospital , Palermo , Italy.
Monica
M
Cannata
a Department of Hematology and Rare Diseases , Unit of Rare Diseases of Blood and Blood-Forming Organs, Villa Sofia-Cervello Hospital , Palermo , Italy and.|b Department of Hematology and Rare Diseases , Unit for Molecular Diagnosis of Rare Diseases, Regional Reference Laboratory for Screening and Prenatal Diagnosis of Hemoglobinopathies, Villa Sofia-Cervello Hospital , Palermo , Italy.
Aurelio
A
Maggio
a Department of Hematology and Rare Diseases , Unit of Rare Diseases of Blood and Blood-Forming Organs, Villa Sofia-Cervello Hospital , Palermo , Italy and.|b Department of Hematology and Rare Diseases , Unit for Molecular Diagnosis of Rare Diseases, Regional Reference Laboratory for Screening and Prenatal Diagnosis of Hemoglobinopathies, Villa Sofia-Cervello Hospital , Palermo , Italy.
Antonino
A
Giambona
D004252:DNA Mutational Analysis; D005817:Genetic Counseling; D006443:Hemoglobin A2; D006451:Hemoglobin, Sickle / Q000235:genetics; D006455:Hemoglobins, Abnormal / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D005810:Multigene Family / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D012042:Registries; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics
D006451:Hemoglobin, Sickle; D006455:Hemoglobins, Abnormal; D055544:beta-Globins; C049102:hemoglobin A2'; D006443:Hemoglobin A2
hemoglobin (Hb); point mutation; screening; single nucleotide (nt) polymorphism (SNP); β-Globin gene