Eleven Cases of Hb J-Paris-I [: c.38C>A (or )]: A Stable α Chain Variant Elutes in the P3 Window on High-Performance Liquid Chromatography.

Hb J-Paris-I [: c.38C>A (or )] is a stable fast-moving hemoglobin (Hb) that elutes in the P3 window on high performance liquid chromatography (HPLC). The mutation can happen on either the α1- or α2-globin gene.

Eight Cases of Hb Winnipeg [: c.226G>T (or )]: A Detailed Study.

Hb Winnipeg [α75(EF4)Asp→Tyr (α2); : c.226G>T (or )] is a stable α-globin chain variant described in a few articles. The majority of reported cases in older articles were clustered in Canada.

Twelve Cases of Hb Manitoba [α102(G9)Ser→Arg]: the Fluctuation in the Variant Expression.

Hb Manitoba [α102(G9)Ser→Arg] is a rare α chain variant with diverse ethnic origins. It is mildly unstable with an expression of around 10.0-14.

Fifteen Cases of Hb J-Meerut: The Rare Association with Hb E and/or : c.-24C>G (or ) Variants.

Hb J-Meerut [: c.362C>A (or )] is a rare, stable, nonpathogenic α-globin gene variant that peaks in the area between the P3 and A windows on high performance liquid chromatography (HPLC). Few cases from different ethnic origins have been published but the majority were Asian Indians.

A Wide Spectrum Study of α-Globin Chain Variants: Cases from the UK.

Over many years, cases of suspected α-globin chain variants were collected from different parts of the UK. The suspicion was based on the clinical picture, high performance liquid chromatography (HPLC) variant percentage, retention time (RT) and isoelectric focusing (IEF). DNA sequencing and the restriction enzyme EI were used for definitive diagnosis.

The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study.

Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21.

Clinical-grade validation of whole genome sequencing reveals robust detection of low-frequency variants and copy number alterations in CLL.

The 100 000 Genome Project aims to develop a diagnostics platform by introducing whole genome sequencing (WGS) into clinical practice. Samples from patients with chronic lymphocytic leukaemia were subjected to WGS. WGS detection of single nucleotide variants and insertion/deletions were validated by targeted next generation sequencing showing high concordance (96·3%), also for detection of sub-clonal variants and low-frequency TP53 variants.

Mutational analysis of disease relapse in patients allografted for acute myeloid leukemia.

Disease relapse is the major cause of treatment failure after allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML). To identify AML-associated genes prognostic of AML relapse post-allo-SCT, we resequenced 35 genes in 113 adults at diagnosis, 49 of whom relapsed. Two hundred sixty-two mutations were detected in 102/113 (90%) patients.

Ten Years of Routine α- and β-Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations.

We review and report here the genotypes and phenotypes of 60 novel thalassemia and abnormal hemoglobin (Hb) mutations discovered following the adoption of routine DNA sequencing of both α- and β-globin genes for all UK hemoglobinopathy samples referred for molecular investigation. This screening strategy over the last 10 years has revealed a total of 11 new β chain variants, 15 α chain variants, 19 β-thalassemia (β-thal) mutations and 15 α(+)-thalassemia (α(+)-thal) mutations. The large number of new thalassemia alleles confirms the wide racial heterogeneity of mutations in the UK immigrant population.

Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL.

Although TP53, NOTCH1, and SF3B1 mutations may impair prognosis of patients with chronic lymphocytic leukemia (CLL) receiving frontline therapy, the impact of these mutations or any other, alone or in combination, remains unclear at relapse. The genome of 114 relapsed/refractory patients included in prospective trials was screened using targeted next-generation sequencing of the TP53, SF3B1, ATM, NOTCH1, XPO1, SAMHD1, MED12, BIRC3, and MYD88 genes. We performed clustering according to both number and combinations of recurrent gene mutations.

A study of δ-globin gene mutations in the UK population: identification of three novel variants and development of a novel DNA test for Hb A'2.

We report here the spectrum of δ-globin gene mutations found in the UK population. Nine different δ chain variants and two δ-thalassemia (δ-thal) mutations were characterized in a study of 127 alleles in patients with either a low Hb A2 value or a split Hb A2 peak on high performance liquid chromatography (HPLC). The most common δ chain variant was Hb [Formula: see text] (or Hb B2) [δ16(A13)Gly → Arg; HBD: c.

SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage.

SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase and a nuclease that restricts HIV-1 in noncycling cells. Germ-line mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal whole genome sequencing study of chronic lymphocytic leukemia (CLL), we revealed a SAMHD1 mutation as a potential founding event.

Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns.

Chronic lymphocytic leukemia is characterized by relapse after treatment and chemotherapy resistance. Similarly, in other malignancies leukemia cells accumulate mutations during growth, forming heterogeneous cell populations that are subject to Darwinian selection and may respond differentially to treatment. There is therefore a clinical need to monitor changes in the subclonal composition of cancers during disease progression.

Prenatal diagnosis of hemoglobinopathies by pyrosequencing: a more sensitive and rapid approach to fetal genotyping.

Prenatal diagnosis of the hemoglobinopathies by fetal DNA analysis is currently performed in most countries, either by DNA sequencing, restriction enzyme polymerase chain reaction (RE-PCR) or the amplification refractory mutation system (ARMS). These methods are time consuming and prolong the turnaround time for diagnosis. We here describe a method utilizing pyrosequencing for the prenatal diagnosis of 12 common nondeletional α- and β-globin gene mutations in the UK population.

Screening for clinically significant non-deletional alpha thalassaemia mutations by pyrosequencing.

Non-deletional α(+)-thalassaemia is associated with a higher degree of morbidity and mortality than deletional forms of α(+)-thalassaemia. Screening for the common deletional forms of α-thalassaemia by Gap-PCR is widely practiced; however, the detection of non-deletional α-thalassaemia mutations is technically more labour-intensive and expensive, as it requires DNA sequencing. In addition, the presence of four very closely homologous alpha globin genes and the frequent co-existence of deletional forms of α-thalassaemia present another layer of complexity in the detection of these mutations.

Multiplex ligation-dependent probe amplification identification of 17 different beta-globin gene deletions (including four novel mutations) in the UK population.

Large deletions of the beta-globin gene cluster are problematic to diagnose, and consequently the frequency and range of these mutations in the UK is unknown. Here we present a study evaluating the efficacy of the recently available technique of multiplex ligation-dependent prob amplification (MLPA) to determine the range and frequency of these deletions in the UK population. The results revealed a large deletion mutation in 75 of 316 patient samples collected over a 3-year period.

Incidence of haemoglobinopathies in various populations - the impact of immigration.

Objectives: The aim of this study was to update the incidence data of beta thalassaemia mutations in various populations and compare it to the spectrum of mutations in the United Kingdom (UK) population in order to determine the impact of immigration.

Design And Methods: Published data for the beta-thalassaemia mutation spectrum and allele frequencies for 60 other countries was updated and collated into regional tables. The beta-thalassaemia mutations in the UK population have been characterised in 1712 unrelated carriers referred for antenatal screening.