Focus on cystic fibrosis and other disorders evidenced in fetuses with sonographic finding of echogenic bowel: 16-year report from Brittany, France.

Objective: Pregnancies medical follow-up and ultrasonography development have enabled detection of fetal echogenic bowel, a sign associated with various pathologies, including cystic fibrosis. Based on the long experience of a region where cystic fibrosis is frequent (Brittany, France), we describe disorders diagnosed in fetal echogenic bowel fetuses and assess ultrasonography ability in detecting cystic fibrosis in utero.

Study Design: We reviewed the cases of fetal echogenic bowel diagnosed in pregnant women living in Brittany and referred for CFTR gene analysis over the 1992-2007 period (n = 289).

Iron metabolism in macrophages from HFE hemochromatosis patients.

HFE-linked hereditary hemochromatosis is a common form of iron-overload disease in European populations. We studied the role of HFE in macrophage iron metabolism. Patients under venesection treatment had higher EPO levels and drastically reduced levels of transferrin receptor (TfRC and TfR2) mRNA, and also decreased levels of HAMP mRNA in macrophages cultured in autologous serum.

Evidence of association between GDF5 polymorphisms and congenital dislocation of the hip in a Caucasian population.

Objective: Congenital dislocation of the hip (CDH) is a multifactorial disease which involves genetic factors that are still unidentified. Recently, a functional polymorphism (rs143383) of the 5'-untranslated region of GDF5 (Growth/Differentiation Factor 5) - previously reported to be associated with osteoarthritis - has been associated with CDH in a Chinese population. The aim of our study was to determine whether GDF5, known to be involved in bone, joint and cartilage morphogenesis, is also associated with CDH in Caucasians.

CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3.

Cystic fibrosis is a prominent genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Among the many disease-causing alterations are pre-mRNA splicing defects that can hamper mandatory exon inclusion. CFTR exon 9 splicing depends in part on a polymorphic UG(m)U(n) sequence at the end of intron 8, which can be bound by TDP-43, leading to partial exon 9 skipping.

Factors influencing disease phenotype and penetrance in HFE haemochromatosis.

Haemochromatosis is predominantly associated with the HFE p.C282Y homozygous genotype, which is present in approximately 1 in 200 people of Northern European origin. However, not all p.

Revealing the human mutome.

The number of known mutations in human nuclear genes, underlying or associated with human inherited disease, has now exceeded 100,000 in more than 3700 different genes (Human Gene Mutation Database). However, for a variety of reasons, this figure is likely to represent only a small proportion of the clinically relevant genetic variants that remain to be identified in the human genome (the 'mutome'). With the advent of next-generation sequencing, we are currently witnessing a revolution in medical genetics.

Genomic rearrangements in inherited disease and cancer.

Genomic rearrangements in inherited disease and cancer involve gross alterations of chromosomes or large chromosomal regions and can take the form of deletions, duplications, insertions, inversions or translocations. The characterization of a considerable number of rearrangement breakpoints has now been accomplished at the nucleotide sequence level, thereby providing an invaluable resource for the detailed study of the mutational mechanisms which underlie genomic recombination events. A better understanding of these mutational mechanisms is vital for improving the design of mutation detection strategies.

Cytogenetics in pre-B and B-cell acute lymphoblastic leukemia: a study of 208 patients diagnosed between 1981 and 2008.

The detection of chromosome abnormalities by conventional cytogenetics, now combined with analyses using fluorescence in situ hybridization (FISH), is an important component in assessing the risk stratification of acute lymphoblastic leukemia (ALL). Identification of specific chromosome abnormalities led to the recognition of genetic subgroups based on modal chromosomal number, reciprocal translocations in B-cell ALL, or both. We report here the cytogenetic analysis of 208 patients with pre-B and B-cell ALL referred to a single laboratory between 1981 and 2008.

Genetic analysis of the glycoprotein 2 gene in patients with chronic pancreatitis.

Objectives: The aim of this study was to evaluate whether variations in the glycoprotein 2 gene (GP2) may potentially affect the risk of chronic pancreatitis.

Methods: Six hundred sixty-one French white patients (idiopathic chronic pancreatitis, n = 590; familial chronic pancreatitis, n = 42; hereditary pancreatitis, n = 29), 445 Dravidian patients from India (tropical calcific pancreatitis, n = 306; idiopathic chronic pancreatitis, n = 139), and 962 unrelated healthy subjects (French white, n = 500; Dravidian, n = 462) participated in this case-control association study. The entire coding sequence of the GP2 gene was searched for conventional genetic variations by direct sequencing, whereas all 12 exons of the GP2 gene were screened for copy number variations by quantitative fluorescent multiplex-polymerase chain reaction.

Philadelphia chromosome-positive acute lymphoblastic leukemia: a cytogenetic study of 33 patients diagnosed between 1981 and 2008.

Background: The Philadelphia (Ph) chromosome, resulting from a t(9;22)(q34;q11), is one of the most frequent chromosomal abnormalities observed among patients with acute lymphoblastic leukemia (ALL). Main of study: To analyze the distribution of Ph chromosome-positive ALL patients.

Patients And Methods: Conventional cytogenetic analysis was performed on bone marrow cells at the time of diagnosis and/or relapse of 208 patients shown to have B-cell ALL.

Complex and cryptic chromosomal rearrangements involving the MLL gene in acute leukemia: a study of 7 patients and review of the literature.

Chromosomal rearrangements involving the MLL gene have been associated with many different types of hematological malignancies. Most of them are easily recognized by conventional cytogenetics. However, in some cases, complex, unusual or cryptic rearrangements make the MLL involvement difficult or impossible to be detected by conventional cytogenetics.

Genetics of osteoporosis: accelerating pace in gene identification and validation.

Osteoporosis is characterized by low bone mineral density and structural deterioration of bone tissue, leading to an increased risk of fractures. It is the most common metabolic bone disorder worldwide, affecting one in three women and one in eight men over the age of 50. In the past 15 years, a large number of genes have been reported as being associated with osteoporosis.

Complete ascertainment of intragenic copy number mutations (CNMs) in the CFTR gene and its implications for CNM formation at other autosomal loci.

Over the last 20 years since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, more than 1,600 different putatively pathological CFTR mutations have been identified. Until now, however, copy number mutations (CNMs) involving the CFTR gene have not been methodically analyzed, resulting almost certainly in the underascertainment of CFTR gene duplications compared with deletions. Here, high-resolution array comparative genomic hybridization (averaging one interrogating probe every 95 bp) was used to analyze the entire length of the CFTR gene (189 kb) in 233 cystic fibrosis chromosomes lacking conventional mutations.

Gene conversion in human genetic disease.

Gene conversion is a specific type of homologous recombination that involves the unidirectional transfer of genetic material from a 'donor' sequence to a highly homologous 'acceptor'. We have recently reviewed the molecular mechanisms underlying gene conversion, explored the key part that this process has played in fashioning extant human genes, and performed a meta-analysis of gene-conversion events known to have caused human genetic disease. Here we shall briefly summarize some of the latest developments in the study of pathogenic gene conversion events, including (i) the emerging idea of minimal efficient sequence homology (MESH) for homologous recombination, (ii) the local DNA sequence features that appear to predispose to gene conversion, (iii) a mechanistic comparison of gene conversion and transient hypermutability, and (iv) recently reported examples of pathogenic gene conversion events.

The calpain, caspase 12, caspase 3 cascade leading to apoptosis is altered in F508del-CFTR expressing cells.

In cystic fibrosis (CF), the most frequent mutant variant of the cystic fibrosis transmembrane conductance regulator (CFTR), F508del-CFTR protein, is misfolded and retained in the endoplasmic reticulum (ER). We previously showed that the unfolded protein response (UPR) may be triggered in CF. Since prolonged UPR activation leads to apoptosis via the calcium-calpain-caspase-12-caspase-3 cascade and because apoptosis is altered in CF, our aim was to compare the ER stress-induced apoptosis pathway between wild type (Wt) and F508del-CFTR expressing cells.

HFE-Related Hemochromatosis: The Haptoglobin 2-2 Type Has a Significant but Limited Influence on Phenotypic Expression of the Predominant p.C282Y Homozygous Genotype.

Phenotypic expression of the common p.C282Y/p.C282Y HFE-related hemochromatosis genotype is heterogeneous and depends on a complex interplay of genetic and non-genetic factors.

Pulmonary outcome differences in U.S. and French cystic fibrosis cohorts diagnosed through newborn screening.

Background: A comparison of the longitudinal progression of lung disease in cystic fibrosis patients identified through newborn screening (NBS) in cohorts located in two different countries has never been performed and was the primary objective of this study.

Methods: The study included 56 patients in Brittany diagnosed through NBS between 1989 and 1994 and 69 similar patients in Wisconsin between 1985 and 1994. The onset and progression of lung disease was radiographically quantified using the Wisconsin Chest X-ray (WCXR) scoring system.

The c.1275A>G putative chronic pancreatitis-associated synonymous polymorphism in the glycoprotein 2 (GP2) gene decreases exon 9 inclusion.

We have recently found that a common synonymous single nucleotide polymorphism (SNP), c.1275A>G, in exon 9 of the glycoprotein 2 (GP2) gene was significantly underrepresented in French idiopathic chronic pancreatitis patients 20years old or younger at disease onset than in the control population. To further investigate to this preliminary genetic finding, we characterized the functionality of c.

The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening.

Background: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas.