Evidence for decline in the incidence of cystic fibrosis: a 35-year observational study in Brittany, France

<p>Abstract</p> <p>Background</p> <p>Cystic fibrosis (CF) is an autosomal recessive disorder whose incidence has long been estimated as 1/2500 live births in Caucasians. Expanding implementation of newborn screening (NBS) programs now allows a better monitoring of the disease incidence, what is essential to make reliable predictions for disease management. This study assessed time trends in the birth incidence of CF over a long period (35 years: 1975-2009) in an area where CF is frequent (Brittany, France) and where NBS has been implemented for more than 20 years.</p> <p>Methods</p> <p>This study enrolled CF patients born in Brittany between January 1^st1975 and December 31^st2009 (n = 483). Time trends in incidence were examined using Poisson regression and mainly expressed using the average percent change (APC).</p> <p>Results</p> <p>The average number of patients born each year declined from 18.6 in the late 1970's (period 1975-79) to 11.6 nowadays (period 2005-09). The corresponding incidence rates dropped from 1/1983 to 1/3268, which represented a decline close to 40% between these two periods (APC = -39.3%, 95% CI = -55.8% to -16.7%, p = 0.0020). A clear breakpoint in incidence rate was observed at the end of the 1980's (p < 0.0001). However, the incidence rate has remained quite stable since that time (annual APC = -1.0%, 95% CI = -3.0% to 1.1%, p = 0.3516).</p> <p>Conclusions</p> <p>This study provides an accurate picture of the evolution of the incidence of a genetic disease over a long period and highlights how it is influenced by the health policies implemented. We observed a 40% drop in incidence in our area which seems consecutive to the availability of prenatal diagnosis.</p

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 under-ascertainment 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. We succeeded in identifying five duplication CNMs that would otherwise have been refractory to analysis. Based upon findings from this and other studies, we propose that deletion and duplication CNMs in the human autosomal genome are likely to be generated in the proportion of approximately 2-3:1. We further postulate that intragenic gene duplication CNMs in other disease loci may have been routinely underascertained. Finally, our analysis of +/-20 bp flanking each of the 40 CFTR breakpoints characterized at the DNA sequence level provide support for the emerging concept that non-B DNA conformations in combination with specific sequence motifs predispose to both recurring and nonrecurring genomic rearrangements. Hum Mutat 31:421-428, 2010. (C) 2010 Wiley-Liss, Inc

A Conservative Assessment of the Major Genetic Causes of Idiopathic Chronic Pancreatitis: Data from a Comprehensive Analysis of PRSS1, SPINK1, CTRC and CFTR Genes in 253 Young French Patients

International audienceIdiopathic chronic pancreatitis (ICP) has traditionally been defined as chronic pancreatitis in the absence of any obvious precipitating factors (e.g. alcohol abuse) and family history of the disease. Studies over the past 15 years have revealed that ICP has a highly complex genetic architecture involving multiple gene loci. Here, we have attempted to provide a conservative assessment of the major genetic causes of ICP in a sample of 253 young French ICP patients. For the first time, conventional types of mutation (comprising coding sequence variants and variants at intron/exon boundaries) and gross genomic rearrangements were screened for in all four major pancreatitis genes, PRSS1, SPINK1, CTRC and CFTR. For the purposes of the study, synonymous, intronic and 5'- or 3'-untranslated region variants were excluded from the analysis except where there was persuasive evidence of functional consequences. The remaining sequence variants/genotypes were classified into causative, contributory or neutral categories by consideration of (i) their allele frequencies in patient and normal control populations, (ii) their presumed or experimentally confirmed functional effects, (iii) the relative importance of their associated genes in the pathogenesis of chronic pancreatitis and (iv) gene-gene interactions wherever applicable. Adoption of this strategy allowed us to assess the pathogenic relevance of specific variants/genotypes to their respective carriers to an unprecedented degree. The genetic cause of ICP could be assigned in 23.7% of individuals in the study group. A strong genetic susceptibility factor was also present in an additional 24.5% of cases. Taken together, up to 48.2% of the studied ICP patients were found to display evidence of a genetic basis for their pancreatitis. Whereas these particular proportions may not be extrapolable to all ICP patients, the approach employed should serve as a useful framework for acquiring a better understanding of the role of genetic factors in causing this oligogenic disease

Polycystic kidney disease associated with intracranial hypertension revealing a mutation of the OFD1 gene

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Pitfalls in the interpretation of CFTR variants in the context of incidental findings

International audienceWhole-exome/genome sequencing analyses lead to detect disease-causing variants that are unrelated to the initial clinical question. Irrespective of any actionable gene list, only pathogenic variants should be considered. The pathogenicity of 55 cystic fibrosis transmembrane conductance regulator (CFTR) variants of known various impacts was assessed by a group of experts by comparing data from specialized databases CFTR-France and CFTR2 with those of general clinical databases ClinVar and Human Gene Mutation Database (HGMD®) Professional and data aggregators VarSome and InterVar. The assessment of cystic fibrosis (CF) variants was correct with ClinVar and HGMD® Professional while less reliable with VarSome and InterVar. Conversely, the risk of overclassifying variants as CF-causing was up to 82% with HGMD® Professional. The concordance between data aggregators was only 50%. The use of general databases and aggregators is thus associated with a substantial risk of misclassifying variants. This evaluation may be extrapolated to other disease conditions and incites to remain cautious in interpreting and disclosing incidental findings

Novel long-range regulatory mechanisms controlling PKD2 gene expression

Abstract Background Cis-regulatory elements control gene expression over large distances through the formation of chromatin loops, which allow contact between enhancers and gene promoters. Alterations in cis-acting regulatory systems could be linked to human genetic diseases. Here, we analyse the spatial organization of a large region spanning the polycystic kidney disease 2 (PKD2) gene, one of the genes responsible of autosomal dominant polycystic kidney disease (ADPKD). Results By using chromosome conformation capture carbon copy (5C) technology in primary human renal cyst epithelial cells, we identify novel contacts of the PKD2 promoter with chromatin regions, which display characteristics of regulatory elements. In parallel, by using functional analysis with a reporter assay, we demonstrate that three DNAse I hypersensitive sites regions are involved in the regulation of PKD2 gene expression. Conclusions Finally, through alignment of CCCTC-binding factor (CTCF) sites, we suggest that these novel enhancer elements are brought to the PKD2 promoter by chromatin looping via the recruitment of CTCF

SO029IDENTIFYING THE CULPRIT GENE IN 400 GENETICALLY UNRESOLVED AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY OR LIVER DISEASE (ADPKD/ADPLD) PEDIGREES

INTRODUCTION AND AIMS: In 7 to 10% of ADPKD patients no mutation of the PKD1 and PKD2 genes is identified. The recent description of GANAB, encoding the α subunit of the glucosidase II, where mutations impair polycystin trafficking, indicate further genic heterogeneity in ADPKD and ADPLD. We hypothesized that, (1)-other genes processing the polycystin proteins are associated with ADPKD/ADPLD, (2)- some patients with other cystic disorders are misdiagnosed as ADPKD, and (3)- that Sanger sequencing misses some PKD1/PKD2 mutations. Our aim is to define the etiology of a cohort of 400 ADPKD-like patients without detected PKD1 or PKD2 mutations

22 ICP patients displaying evidence of a digenic inheritance pattern.

<p>In <i>PRSS1</i>, <i>SPINK1</i> and <i>CTRC</i>, the variants or genotypes classified variously as causative, contributory or neutral are given in red, blue and black, respectively. In <i>CFTR</i>, the alleles classified individually as severe, mild or associated with CFTR-related disorders, and neutral are in green, violet and black, respectively. See text for details regarding the definition of causative, contributory and neutral <i>CFTR</i> genotypes and gene-gene interactions.</p

The “salt and pepper” pattern on renal ultrasound in a group of children with molecular-proven diagnosis of ciliopathy-related renal diseases

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