Molecular characterization of novel and rare DNA variants in patients with galactosemia.

Galactosemia is an inherited disorder caused by mutations in the three genes that encode enzymes implicated in galactose catabolism. Currently, the only available treatment for galactosemia is life-long dietary restriction of galactose/lactose, and despite treatment, it might result in long-term complications. Here, we present five cases of newborn patients with elevated galactose levels, identified in the context of the newborn screening program.

Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach.

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system.

First report of Hb A2-NYU (HBD:c.39T>A) in the Hellenic population.

We report the first heterozygous case of Hb A(2)-NYU (HBD:c.39T>A) in the Hellenic population. The proband, an adult female from the island of Crete, Greece, was identified during routine family screening.

The 5' regulatory region of the human fetal globin genes is a gene conversion hotspot.

The human fetal globin genes consist of the first mammalian genomic loci for which gene conversion was reported. To date, 14 gene conversions have been described in the human Ggamma- and Agamma-globin genes, the vast majority of which are restricted to the coding sequences. Here, we provide evidence for three new gene conversion events in the 5' regulatory region of the human fetal globin genes, identified during a large genetic screening effort in adult individuals with high fetal hemoglobin (Hb) levels.

The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the HBG2 gene promoter.

Nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH), a rare hereditary condition resulting in elevated levels of fetal hemoglobin (Hb F) in adults, is associated with promoter mutations in the human fetal globin (HBG1 and HBG2) genes. In this paper, we report a novel type of nd-HPFH due to a HBG2 gene promoter mutation (HBG2:g.-109G>T).

A versatile denaturing HPLC approach for human beta-globin gene mutation screening.

Hemoglobinopathies represent the most common genetic disorder worldwide, with a higher prevalence among populations with a history of malaria endemicity. More than 690 mutations in the human beta-globin gene are usually the cause of beta-type hemoglobinopathies. Here, we report a rapid and highly sensitive beta-globin gene mutation screening approach based on denaturing high-performance liquid chromatography (DHPLC), which contrary to the previously described ones can be used in every HPLC apparatus.

Evidence for the molecular heterogeneity of sickle cell anemia chromosomes bearing the betaS/Benin haplotype.

There are at least four distinct African and one Asian chromosomal backgrounds (haplotypes) on which the sickle cell mutation has arisen. Additionally, previous data suggest that the beta(S)/Bantu haplotype is heterogeneous at the molecular level. Here, we report the presence of the (A)gamma -499 T-->A variation in sickle cell anemia chromosomes of Sicilian and North African origin bearing the beta(S)/Benin haplotype.

Molecular diagnosis of inherited disorders: lessons from hemoglobinopathies.

Hemoglobinopathies constitute a major health problem worldwide, with a high carrier frequency, particularly in certain regions where malaria has been endemic. These disorders are characterized by a vast clinical and hematological phenotypic heterogeneity. Over 1,200 different genetic alterations that affect the DNA sequence of the human alpha-like (HBZ, HBA2, HBA1, and HBQ1) and beta-like (HBE1, HBG2, HBG1, HBD, and HBB) globin genes are mainly responsible for the observed clinical heterogeneity.

Hellenic National Mutation database: a prototype database for mutations leading to inherited disorders in the Hellenic population.

The exponential discovery rate of new genomic alterations, leading to inherited disorders, as well as the need for comparative studies of different population's mutation frequencies necessitates recording their population-wide spectrum in online mutation databases. We report the construction of the Hellenic National Mutation database (http://www.goldenhelix.

Molecular characterization and diagnosis of Hb Crete [beta129(H7)Ala-->Pro].

We report the molecular characterization of Hb Crete [beta129(H7)Ala-->Pro] in a female subject from the Greek island of Crete. DNA sequence analysis revealed a 1368 GCC-->CCC base substitution in exon 3 of the beta-globin gene, leading to the Ala-->Pro amino acid change at codon 129. Both the proband and her mother, who were found to be heterozygotes for Hb Crete, presented with mild microcytic anemia and normal Hb A2 levels and iron metabolism indices.

A comparative study of Greek nondeletional hereditary persistence of fetal hemoglobin and beta-thalassemia compound heterozygotes.

The coexistence of beta- and gamma-globin gene mutations in the compound heterozygous state presents a rare in vivo model that provides important data on gene regulation of clinical interest. In this unique comparative study we present the hematological, biosynthetic, and molecular data from six adult compound heterozygotes for the Greek nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH, Agamma-117 G-->A) and four frequent beta-thalassemia mutations (IVS I-110 G-->A, Cd 39 C-->T, IVS I-1 G-->A, and IVS I-6 T-->C) found in the Hellenic population. Fetal hemoglobin (HbF) levels were found to be considerably higher (25-50%) than in 19 Greek nd-HPFH heterozygotes (HbF=9.