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.

Twenty-five novel mutations including duplications in the ATP7A gene.

Twenty-five novel mutations including duplications in the ATP7A gene. Menkes disease (MD) and occipital horn syndrome (OHS) are allelic X-linked recessive copper deficiency disorders resulting from ATP7A gene mutations. MD is a severe condition leading to progressive neurological degeneration and death in early childhood, whereas OHS has a milder phenotype with mainly connective tissue abnormalities. Until now, molecular analyses have revealed only deletions and point mutations in both diseases. This study reports new molecular data in a series of 40 patients referred for either MD or OHS. We describe 23 point mutations (9 missense mutations, 7 splice site variants, 4 nonsense mutations, and 3 small insertions or deletions) and 7 intragenic deletions. Of these, 18 point mutations and 3 deletions are novel. Furthermore, our finding of four whole exon duplications enlarges the mutation spectrum in the ATP7A gene. ATP7A alterations were found in 85% of cases. Of these alterations, two thirds were point mutations and the remaining one third consisted of large rearrangements. We found that 66.6% of point mutations resulted in impaired ATP7A transcript splicing, a phenomenon more frequent than expected. This finding enabled us to confirm the pathogenic role of ATP7A mutations, particularly in missense and splice site variants.