ABSTRACT
Newborn screening identified a Chinese-Canadian infant who was positive for possible ß-thalassemia (ß-thal). Detailed family studies demonstrated that the proband was a compound heterozygote for the Chinese Gγ(Aγδß)0-thal deletion and a novel frameshift mutation within exon 3 (HBB:c.336dup), and heterozygous for the Southeast Asian α-thal deletion (--SEA/αα). This case illustrates the importance of follow-up molecular testing of positive newborn screening results to confirm the diagnosis and define risks for future pregnancies.
Subject(s)
Genotype , Neonatal Screening , beta-Globins , beta-Thalassemia , Female , Humans , Infant, Newborn , Male , beta-Globins/genetics , beta-Thalassemia/genetics , beta-Thalassemia/diagnosis , Frameshift Mutation , Heterozygote , Mutation , PedigreeABSTRACT
We report two hemoglobinopathy cases involving a novel ß-thalassemia (ß-thal) nonsense mutation, HBB:c.199A > T. One patient had Hb S/ß-thal, and a second unrelated patient had Hb D-Punjab/ß-thal. The HBB:c.199A > T mutation introduces a premature termination codon at amino acid codon 66 (AAAâTAA) in exon 2, resulting in typical high Hb A2 ß0-thal.
Subject(s)
Hemoglobinopathies , beta-Thalassemia , Humans , beta-Globins/genetics , beta-Thalassemia/diagnosis , beta-Thalassemia/genetics , Codon, Nonsense , Hemoglobinopathies/genetics , MutationABSTRACT
We report a case of Hb S/ß0-thalassemia (Hb S/ß0-thal) in a patient who is a compound heterozygote for the Hb Sickle mutation (HBB:c.20A > T) and a mutation of the canonical splice acceptor sequence of IVS1 (AG > TG, HBB:c.93-2A > T). This is the fifth mutation involving the AG splice acceptor site of IVS1, all of which prevent normal splicing and cause ß0-thal.
Subject(s)
Hemoglobin, Sickle , Mutation , RNA Splice Sites , beta-Thalassemia , Humans , beta-Thalassemia/genetics , beta-Thalassemia/diagnosis , beta-Thalassemia/blood , Hemoglobin, Sickle/genetics , beta-Globins/genetics , Male , Heterozygote , Anemia, Sickle Cell/genetics , Anemia, Sickle Cell/diagnosis , FemaleABSTRACT
Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs.
ABSTRACT
We report two novel ß-thalassemia (ß-thal) deletions involving the 5' region of the ß-globin gene (HBB). The first deletion spans 538 bp and removes the ß-globin promoter, 5' untranslated region (5'UTR) and most of exon 1. This deletion was identified in a 3-year-old Vietnamese boy with non transfusion dependent Hb E (HBB: c.79G>A)/ß0-thal. The second deletion spans 1517 bp and removes the ß-globin gene promoter, 5'UTR, and exons 1 and 2. This deletion was identified in two unrelated adults of European descent who had ß-thal trait with unusually high Hb A2 levels. Deletions such as these are generally associated with higher levels of Hb A2 and Hb F than typical ß-thal alleles, which may ameliorate the severity of the disease.
Subject(s)
3' Untranslated Regions , Base Sequence , Promoter Regions, Genetic , Sequence Deletion , beta-Globins/genetics , beta-Thalassemia/genetics , Child, Preschool , Female , Humans , MaleABSTRACT
We report an α0-thalassemia (α0-thal) trait in Newfoundlanders caused by a novel 90.7 kb deletion. The deletion, designated the Newfoundland deletion (- -NFLD), removes both the HBA2 and HBA1 genes, while leaving the HBZ gene intact. The 5' deletion endpoint is within the HBAP1 pseudogene, approximately 3.7 kb upstream of the HBA2 gene. The 3' deletion endpoint is approximately 82.5 kb downstream of the HBA1 gene, within the second intervening sequence (IVS-II) of the FAM234A gene. This is the second α0-thal deletion reported in Newfoundland families of northern European descent.
Subject(s)
Sequence Deletion , alpha-Globins/genetics , alpha-Thalassemia/genetics , Adult , Base Sequence , Female , Genetic Association Studies , Humans , Phenotype , Polymerase Chain Reaction , Sequence Analysis, DNA , alpha-Thalassemia/diagnosisABSTRACT
We report two Italian-Canadian families with α+-thalassemia (α+-thal) trait caused by a novel mutation of the translation initiation codon of the α1-globin gene (ATG>AAG or HBA1:c.2T>A). This is the tenth reported α-thal mutation involving the translation initiation codon or the conserved Kozak consensus sequences of the HBA2 or HBA1 genes.
Subject(s)
Codon, Initiator/genetics , Mutation , alpha-Globins/genetics , Canada/epidemiology , Consensus Sequence/genetics , Family , Glycated Hemoglobin/genetics , Hemoglobin A2/genetics , Humans , Italy/ethnology , alpha-Thalassemia/geneticsABSTRACT
We report a case of δß-thalassemia (δß-thal) trait in an adult male originally from Sudan. Multiplex ligation-dependent probe amplification (MLPA) was used to localize the approximate boundaries of the deletion, followed by polymerase chain reaction (PCR) amplification and sequence analysis of the junction fragment to determine the precise deletion endpoints. The deletion spans 9594 bp, with the 5' deletion endpoint located 1560 bp upstream of the δ-globin gene and the 3' endpoint within the second intervening sequence (IVS-II) of the ß-globin gene.
Subject(s)
Mutation , beta-Globins/genetics , beta-Thalassemia/diagnosis , beta-Thalassemia/genetics , delta-Globins/genetics , delta-Thalassemia/diagnosis , delta-Thalassemia/genetics , Adult , Base Sequence , DNA Mutational Analysis , Genotype , Humans , Introns , Male , Phenotype , Sequence Deletion , Sudan , beta-Globins/chemistry , delta-Globins/chemistryABSTRACT
We report a case of α(+)-thalassemia (α(+)-thal) trait in a Chinese-Canadian family caused by a novel frameshift mutation of the α2-globin gene, specifically the duplication of a single nucleotide at amino acid codon 56 [HBA2: c.168dup]. The mutation results in substitution of a termination codon (TAA) for lysine (AAG) at amino acid position 56.
Subject(s)
Frameshift Mutation , alpha-Globins/genetics , alpha-Thalassemia/genetics , Adult , Codon , DNA Mutational Analysis , Erythrocyte Indices , Exons , Female , Genotype , Humans , Infant , Male , Phenotype , alpha-Thalassemia/diagnosisSubject(s)
Anemia, Sickle Cell/genetics , Hemoglobin, Sickle/genetics , Locus Control Region , Sequence Deletion , beta-Globins/genetics , beta-Thalassemia/genetics , Anemia, Sickle Cell/diagnosis , Base Sequence , Child , Chromosome Mapping , Genetic Association Studies , Heterozygote , Humans , Male , Molecular Sequence Data , Multigene Family , Mutation , Phenotype , beta-Thalassemia/diagnosisABSTRACT
The -83 (G > A) mutation of the ß-globin gene promoter (HBB: c.-133G > A) was first reported in an adult male patient with mild thalassemic indices, suggesting that this may be a mild ß(+)-thalassemia (ß(+)-thal) allele. In this report, we present data from several patients who are simple heterozygotes for the -83 mutation, or compound heterozygotes for -83 and Hb S (HBB: c.20A > T) or ß-thal. These cases illustrate that the -83 sequence variant is not associated with a thalassemic phenotype. This has important implications for carrier screening and genetic counseling, particularly since the -83 mutation is relatively common in African and Hispanic populations.