Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models.

A large fraction of genome variation between individuals is comprised of submicroscopic copy number variation of genomic DNA segments. We assessed the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes with mouse models of Smith-Magenis and Potocki-Lupski syndromes. We phenotyped mice with 1n (Deletion/+), 2n (+/+), 3n (Duplication/+), and balanced 2n compound heterozygous (Deletion/Duplication) copies of the same region. Parallel to the observations made in humans, such variation in gene copy number was sufficient to generate phenotypic consequences: in a number of cases diametrically opposing phenotypes were associated with gain versus loss of gene content. Surprisingly, some neurobehavioral traits were not rescued by restoration of the normal gene copy number. Transcriptome profiling showed that a highly significant propensity of transcriptional changes map to the engineered interval in the five assessed tissues. A statistically significant overrepresentation of the genes mapping to the entire length of the engineered chromosome was also found in the top-ranked differentially expressed genes in the mice containing rearranged chromosomes, regardless of the nature of the rearrangement, an observation robust across different cell lineages of the central nervous system. Our data indicate that a structural change at a given position of the human genome may affect not only locus and adjacent gene expression but also "genome regulation." Furthermore, structural change can cause the same perturbation in particular pathways regardless of gene dosage. Thus, the presence of a genomic structural change, as well as gene dosage imbalance, contributes to the ultimate phenotype.

Treatment of congenital aortic valve stenosis: impact of the Ross operation.

GOAL: To evaluate the impact of the Ross operation, recently (1997) introduced in our unit, for the treatment of patients with congenital aortic valve stenosis. METHODS: The period from January 1997 to December 2000 was compared with the previous 5 years (1992-96). Thirty-seven children (< 16 yrs) and 49 young adults (16-50 yrs) with congenital aortic valve stenosis underwent one of these treatments: percutaneous balloon dilatation (PBD), aortic valve commissurotomy, aortic valve replacement and the Ross operation. The Ross operation was performed in 16 patients, mean age 24.5 yrs (range 9-46 yrs) with a bicuspid stenotic aortic valve, 7/10 adults with calcifications, 2/10 adults with previous aortic valve commissurotomy, 4/6 children with aortic regurgitation following PBD, and 1/6 children who had had a previous aortic valve replacement with a prosthetic valve and aortic root enlargement. RESULTS: PBD was followed by death in two neonates (fibroelastosis); all other children survived PBD. Although there were no deaths, PBD in adults was recently abandoned, owing to unfavourable results. Aortic valve commissurotomy showed good results in children (no deaths). Aortic valve replacement, although associated with good results (no deaths), has been recently abandoned in children in favour of the Ross operation. Over a mean follow-up of 16 months (2-40 months) all patients are asymptomatic following Ross operation, with no echocardiographic evidence of aortic valve regurgitation in 10/16 patients and with trivial regurgitation in 6/16 patients. CONCLUSIONS: The approach now for children and young adults with congenital aortic valve stenosis should be as follows: (1) PBD is the first choice in neonates and infants; (2) Aortic valve commissurotomy is the first choice for children, neonates and infants after failed PBD; (3) The Ross operation is increasingly used in children after failed PBD and in young adults, even with a calcified aortic valve.

Ross procedure: is the root replacement technique superior to the sub-coronary implantation technique? Long-term results.

There is controversy over the use of the Ross procedure with regard to the sub-coronary and root replacement technique and its long-term durability. A systematic review of the literature may provide insight into the outcomes of these two surgical subvariants. A systematic review of reports between 1967 and February 2013 on sub-coronary and root replacement Ross procedures was undertaken. Twenty-four articles were included and divided into (i) sub-coronary technique and (ii) root replacement technique. The 10-year survival rate for a mixed-patient population in the sub-coronary procedure was 87.3% with a 95% confidence interval (CI) of 79.7-93.4 and 89.1% (95% CI, 85.3-92.1) in the root replacement technique category. For adults, it was 94 vs 95.3% (CI, 88.9-98.1) and in the paediatric series it was 90 vs 92.7% (CI, 86.9-96.0), respectively. Freedom from reoperation at 10 years was, in the mixed population, 83.3% (95% CI, 69.9-93.4) and 93.3% (95% CI, 89.4-95.9) for sub-coronary versus root replacement technique, respectively. In adults, it was 98 vs 91.2% (95% CI, 82.4-295.8), and in the paediatric series 93.3 vs 92.0% (95% CI, 86.1-96.5) for sub-coronary versus root replacement technique, respectively. The Ross procedure arguably has satisfactory results over 5 and 10 years for both adults and children. The results do not support the advantages of the sub-coronary technique over the root replacement technique. Root replacement was of benefit to patients undergoing reoperations on neoaorta and for long-term survival in mixed series.