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Telomere biology disorders are complex clinical conditions that arise due to mutations in genes required for telomere maintenance. Telomere length has been utilised as part of the diagnostic work-up of patients with these diseases; here, we have tested the utility of high-throughput STELA (HT-STELA) for this purpose. HT-STELA was applied to a cohort of unaffected individuals (n = 171) and a retrospective cohort of mutation carriers (n = 172). HT-STELA displayed a low measurement error with inter- and intra-assay coefficient of variance of 2.3% and 1.8%, respectively. Whilst telomere length in unaffected individuals declined as a function of age, telomere length in mutation carriers appeared to increase due to a preponderance of shorter telomeres detected in younger individuals (< 20 years of age). These individuals were more severely affected, and age-adjusted telomere length differentials could be used to stratify the cohort for overall survival (Hazard Ratio = 5.6 (1.5–20.5); p < 0.0001). Telomere lengths of asymptomatic mutation carriers were shorter than controls (p < 0.0001), but longer than symptomatic mutation carriers (p < 0.0001) and telomere length heterogeneity was dependent on the diagnosis and mutational status. Our data show that the ability of HT-STELA to detect short telomere lengths, that are not readily detected with other methods, means it can provide powerful diagnostic discrimination and prognostic information. The rapid format, with a low measurement error, demonstrates that HT-STELA is a new high-quality laboratory test for the clinical diagnosis of an underlying telomeropathy. [ABSTRACT FROM AUTHOR]

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management. Familial myeloid malignancies have recently been classified as separate disease entities. Here, using whole-exome sequencing of affected pedigrees - the authors highlight genetic variants associated with these conditions. [ABSTRACT FROM AUTHOR]

The aim of this study is to present the limbal stem cell deficiency (LSCD) cases with features resembling dyskeratosis congenita (DC), a heritable disease of stem cells principally caused by telomerase deficiency. The clinical, laboratory and molecular findings of four cases are presented. A complete systemic examination was performed in a standardized manner for each patient. Laboratory measurements included investigations of the tests used for screening DC. All eight known disease-causing genes in DC ( DKC1, TERC, TERT, NOP10, NHP2, TINF2, C16orf57, and TCAB1) were screened for mutations. The family members of the cases were also assessed, when possible. In all four patients, multisystem involvement was present, along with the disorder affecting corneal LSCs. The affected tissues were mainly the skin and its adnexa, the oral cavity and the hematopoietic system, which are rapidly renewing tissues, consistent with the presence of a stem cell disorder. Similarly affected cases were seen in different generations in families, suggesting an underlying inherited disorder. No mutation was detected in any of the known disease-causing genes in these patients. Based on the presented cases and with the contribution of the review of previously reported DC cases available, we suggest that DC is one of the inherited causes of LSCD and that those cases presenting with LSCD might represent a subgroup of DC caused by mutations in an as yet undefined gene. [ABSTRACT FROM AUTHOR]

Investigates the targeted disruption of DKC1 gene encoding dyskerin in dyskeratosis congenita. Information on dyskerin; Details on the experiment; Results of the experiment.

Reports on the mutation of the RNA component of telomerase in autosomal dominant dyskeratosis congenita, a progressive bone-marrow failure syndrome. Characteristics of dyskeratosis congenita; X-linked form of the disease due to mutations; Mapping of the gene responsible for dyskeratosis congenita in a large pedigree with autosomal dominant inheritance.

Dyskeratosis congenita (DC) is characterised by the failure of those tissues that are rapidly dividing in the adult, particularly the skin and haemopoietic system. The X-linked form of the disease is caused by mutations in the DKC1 gene. To date the only DKC1 mutations detected result in alterations in the amino acid sequence of dyskerin. Dyskerin is the catalytic subunit of the H+ACA box small nucleolar RNA particles responsible for the site-specific pseudouridination of rRNA and in humans is also a component of the telomerase complex. In order to further characterise the disease at the molecular level, male DC patients from 25 families were screened for mutations in the DKC1 gene. Sequence variations were detected in 10 of these families. In five families, previously identified mutations were detected. Of the five novel sequence changes, three were coding changes: R158 W, S280R and P384L. A fourth sequence change was detected in the 5'-flanking region that disrupts a putative Sp1 transcription factor binding site. An intronic change was also detected that resulted in the partial incorporation of a portion of intron 1 into the mRNA. The identification of this mutation highlights the importance of screening for mutations that cause the partial aberrant splicing of mRNA. This is the first report of DKC1 mutations that are predicted to affect the level of expression of dyskerin. This suggests that a decrease in the amount of the normal protein may cause the disease. [ABSTRACT FROM AUTHOR]

The electrophoretic mobility and level of enzyme activity of glucose-6-phosphate dehydrogenase (G6PD) was established in 100 unrelated Algerian males with G6PD deficiency. DNA from these subjects was analysed for the presence of certain known G6PD mutations by the appropriate restriction enzyme digestion of fragments amplified by the polymerase chain reaction. Where the mutation could not be identified in this way, the samples were subjected to single-strand conformation polymorphism analysis and abnormal fragments were sequenced. In this way, eight different mutations have been identified, of which five are polymorphic and account for 92% of the samples. The most common variants are G6PD A-(46%) and G6PD Mediterranean (23%), both of which were associated with favism. A new polymorphic variant, G6PD Aures, has been identified during the course of this study, whereas another, G6PD Santamaria, has now been established as a polymorphic variant (11%). Thus, G6PD deficiency in Algeria is heterogeneous, suggesting that there has been significant gene flow, both from sub-Saharan Africa and from other parts of the Mediterranean. [ABSTRACT FROM AUTHOR]

Glucose-6-phosphate dehydrogenase (G6PD) deficiency protects from severe forms of malaria. It is interesting therefore to analyze the molecular basis underlying G6PD deficiency in regions such as the Mediterranean basin where malaria was present for a long time in history. Here we report on the genetic characterization of G6PD deficiency among inhabitants of one Mediterranean region—the Dalmatian region of south Croatia. We analyzed 24 unrelated G6PD-deficient male subjects. Molecular testing revealed several different mutations: G6PD Cosenza 9, G6PD Mediterranean 4, G6PD Seattle 3, G6PD Union 3, and G6PD Cassano 1. Furthermore, we have identified one novel G6PD variant that we named G6PD Split. This variant is caused by a nucleotide change 1442 C→G leading to the amino acid substitution 481 Pro→Arg and is characterized by moderate enzyme deficiency (class III variant). This study reveals a higher prevalence (37.5%) of the Cosenza mutation in the Dalmatian region than anywhere else previously investigated and overall shows the considerable molecular heterogeneity underlining G6PD deficiency that can be observed in Mediterranean populations. [ABSTRACT FROM AUTHOR]

Telomerase is a ribonucleoprotein complex that is required to synthesize DNA repeats at the ends of each chromosome. The RNA component of this reverse transcriptase is mutated in the hone marrow failure syndrome autosomal dominant dyskeratosis congenita. Here we show that disease anticipation is observed in families with this disease and that this is associated with progressive telomere shortening. [ABSTRACT FROM AUTHOR]

The article offers updates on the clinical utility gene card for dyskeratosis congenita for 2015. It provides information on the disease characteristics and gene structure with details on the genes or DNA/chromosome segments, analytical methods and validation, and disease prevalence. It also discusses the clinical utility and risk assessment of in the aspect of family heredity through genetic testing.

The Jews of Kurdistan are a small inbred population with a high incidence of β-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Recently, it was reported that the β-thalassaemia in this population shows an unusual mutational diversity; 13 different mutations were identified, of which 4 had not previously been observed in any other population. In contrast, we now report that the G6PD deficiency, which has the highest known incidence in the world, and which affects about 70% of males, is almost entirely attributable to a single widespread mutation, G6PD Mediterranean. [ABSTRACT FROM AUTHOR]

The site of a PvuII restriction fragment length polymorphism (RFLP) of the human glucose-6-phosphate dehydrogenase (G6PD) gene has been located in intron V, 60 bp upstream of G6PD exon VI. A population survey shows this RFLP to be specific for African populations, with frequencies of the rarer allele ( PvuII type 2 site present) of 0.32-0.40 in Kenyans, Nigerians, Zambians, and West Indians. This allele has not been found in the European, Asian and Middle Eastern populations studied. Such population-specific markers may be useful in the study of population affinities and may provide insight into prehistoric migrations of peoples. [ABSTRACT FROM AUTHOR]

The article offers information on genetic testing for dyskeratosis congenital (DC). It presents a series of questions that should be answered prior to the administration of genetic testing which include the effect of disease management to test result, effect of the test result to lifestyle and prevention, and the effectiveness of the test in resolving genetic situation in the family. It mentions that telomere length measurement can be considered as good screening test for DC.