Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey.

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.

The deltaccr5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe.

The chemokine receptor CCR5 is encoded by the CMKBR5 gene located on the p21.3 region of human chromosome 3, and constitutes the major co-receptor for the macrophage-tropic strains of HIV-1. A mutant allele of the CCR5 gene, Delta ccr5 , was shown to provide to homozygotes with a strong resistance against infection by HIV. The frequency of the Delta ccr5 allele was investigated in 18 European populations. A North to South gradient was found, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%). Highly polymorphic microsatellites (IRI3.1, D3S4579 and IRI3.2, D3S4580 ) located respectively 11 kb upstream and 68 kb downstream of the CCR5 gene deletion were used to determine the haplotype of the chromosomes carrying the Delta ccr5 variant. A strong linkage disequilibrium was found between Delta ccr5 and specific alleles of the IRI3.1 and IRI3.2 microsatellites: >95% of the Delta ccr5 chromosomes carried the IRI3.1-0 allele, while 88% carried the IRI3.2-0 allele. These alleles were found respectively in only 2 or 1.5% of the chromosomes carrying a wild-type CCR5 gene. From these data, it was inferred that most, if not all Delta ccr5 alleles originate from a single mutation event, and that this mutation event probably took place a few thousand years ago in Northeastern Europe. The high frequency of the Delta ccr5 allele in Caucasian populations cannot be explained easily by random genetic drift, suggesting that a selection advantage is or has been associated with homo- or heterozygous carriers of the Delta ccr5 allele.

Cystic fibrosis: production of high levels of uromodulin-like protein by HLA-DR blood monocytes differentiating towards a fibroblastic phenotype.

We report here the spontaneous in vitro transformation of blood monocytes into fibroblasts, in a patient suffering from cystic fibrosis (CF). The blood monocytes with this capacity express HLA-DR specificity. Monocytes were identified by non-specific esterase activity and by immunofluorescence using monoclonal antibodies against monocytes/macrophages antigens. Neo-fibroblasts were identified by electron microscopy and immunofluorescence using monoclonal antibodies against a cytoplasmic enzyme specifically involved in the synthesis of collagen. The secretion of collagen was evidenced using antibodies against type I collagen. Both monocytes/macrophages and neo-fibroblasts express the monocytic and the fibroblastic markers and synthesize type I collagen. This transformation observed in vitro might mimick the process of fibrosis development which takes place in vivo, particularly in pancreatic acini, lungs and intestine of patients with CF. Interestingly, the whole process in vitro is inhibited when T lymphocytes are properly stimulated by IL2. In addition, both monocytes and neo-fibroblasts secrete high quantities of uromodulin-like glycoprotein. The significance of this finding is discussed in relation to the thick mucus secretion which characterizes the disease. In addition, from a fundamental point of view, it confirmed in a large series of patients that this observation may have significant implications, since CF mutation impairs the gene coding for cAMP-regulated Cl- channel and that it has been proposed that uromodulin might be implicated in Cl- transport. Therefore the question of the relationships between uromodulin and the cAMP-regulated Cl- channel arises.

[Anti-perinuclear antibodies in the diagnosis and prognosis of rheumatoid polyarthritis]. / Intérêt des anticorps anti-périnucléaires dans le diagnostic et le pronostic de la polyarthrite rhumatoïde.

Anti-perinuclear antibodies (APN) were studied in 547 subjects, 123 of whom suffered from rheumatoid polyarthritis (RP). They were detected 88 times in the latter group (72 percent). 26 percent of RP were without serological abnormalities when only rheumatoid factors were considered (latex, Waaler-Rose, Waaler-Rose LOR, rheumatoid factors by indirect immunofluorescence). The rate dropped to 10 percent when APN were included. This test is therefore sensitive. It is also specific as APN exists in only 11 percent of non-rheumatoid rheumatological diseases not including psoriasis (42 percent) and in 16 percent of other auto-immune diseases. In addition, there is a correlation (p less than 0.01) between APN level and the evolution of the rheumatoid illness. APN appears early in an illness and is thus of diagnostic and prognostic interest in RP.

[Salivary lysozyme, immunoglobulins and beta 2-microglobulin in Gougerot-Sjögren syndrome]. / Lysozyme, immunoglobulines et beta 2 microglobuline salivaire au cours du syndrome de Gougerot-Sjögren.

Lysozyme (LZM), immunoglobulins and beta 2-microglobulin concentrations were measured in the saliva of 79 patients with primary (n = 29) or secondary (n = 50) Sjögren's syndrome and in a control population. beta 2-microglobulin and immunoglobulins A, G and M concentrations were higher, and LZM concentrations lower than in controls. A significant correlation was established between LZM and immunoglobulins, but no correlation was found between immunoglobulins and beta 2-microglobulin, nor between the latter and LZM. These results indicate that salivary LZM concentration may be of value in the diagnosis of Sjögren's syndrome.