Breakpoint mapping and array CGH in translocations: comparison of a phenotypically normal and an abnormal cohort

We report the analyses of breakpoints in 31 phenotypically normal and 14 abnormal carriers of balanced translocations. Our study assesses the differences between balanced translocations in normal carriers and those in abnormal carriers, focusing on the presence of genomic imbalances at the breakpoints or elsewhere in the genome, presence of cryptic chromosome rearrangements, and gene disruption. Our hypothesis is that all four features will be associated with phenotypic abnormalities and absent or much less frequent in a normal population. In the normal cohort, we identified neither genomic imbalances at the breakpoints or elsewhere in the genome nor cryptic chromosome rearrangements. In contrast, we identified candidate disease-causing imbalances in 4/14 abnormal patients. These were three breakpoint associated deletions and three deletions unrelated to the breakpoints. All six de novo deletions originated on the paternally inherited chromosome. Additional complexity was also present in one of these cases. Gene disruption by the breakpoints was present in 16/31 phenotypically normal individuals and in 5/14 phenotypically abnormal patients. Our results show that translocations in phenotypically abnormal patients are molecularly distinct from those in normal individuals: the former are more likely to be associated with genomic imbalances at the breakpoints or elsewhere and with chromosomal complexity, whereas the frequency of gene disruption is similar in both normal and abnormal translocation carrier

Selection criteria for patients with chronic ankle instability in controlled research: a position statement of the International Ankle Consortium

Item does not contain fulltextWhile research on chronic ankle instability (CAI) and awareness of its impact on society and health care systems has grown substantially in the last 2 decades, the inconsistency in participant/patient selection criteria across studies presents a potential obstacle to addressing the problem properly. This major gap within the literature limits the ability to generalise this evidence to the target patient population. Therefore, there is a need to provide standards for patient/participant selection criteria in research focused on CAI with justifications using the best available evidence. The International Ankle Consortium provides this position paper to present and discuss an endorsed set of selection criteria for patients with CAI based on the best available evidence to be used in future research and study designs. These recommendations will enhance the validity of research conducted in this clinical population with the end goal of bringing the research evidence to the clinician and patient

The complex nature of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes

Objective: To describe the systematic analysis of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes, characterise the structural chromosome rearrangements, map the translocation breakpoints, and report detectable genomic imbalances.Methods: DNA microarrays were used with a resolution of 1 Mb for the detailed genome-wide analysis of the patients. Array CGH was used to screen for genomic imbalance and array painting to map chromosome breakpoints rapidly. These two methods facilitate rapid analysis of translocation breakpoints and screening for cryptic chromosome imbalance. Breakpoints of rearrangements were further refined (to the level of spanning clones) using fluorescence in situ hybridisation where appropriate.Results: Unexpected additional complexity or genome imbalance was found in six of 10 patients studied. The patients could be grouped according to the general nature of the karyotype rearrangement as follows: (A) three cases with complex multiple rearrangements including deletions, inversions, and insertions at or near one or both breakpoints; (B) three cases in which, while the translocations appeared to be balanced, microarray analysis identified previously unrecognised imbalance on chromosomes unrelated to the translocation; (C) four cases in which the translocation breakpoints appeared simple and balanced at the resolution used.Conclusions: This high level of unexpected rearrangement complexity, if generally confirmed in the study of further patients, will have an impact on current diagnostic investigations of this type and provides an argument for the more widespread adoption of microarray analysis or other high resolution genome-wide screens for chromosome imbalance and rearrangement

Impact of muscle activation on ranges of motion during active elbow movement in children with spastic hemiplegic cerebral palsy

Background Children with spastic hemiplegic cerebral palsy are restricted in their daily activities due to limited active ranges of motion of their involved upper limb, specifically at the elbow. Their impaired muscles are frequently targeted by anti-spastic treatments that reduce muscle tone. But these treatments do not necessarily improve the limb function. There is a lack of comprehensive knowledge of the quantitative relations between muscle activation and joint active ranges of motion. Consequently, the objective of this study is to quantify the impact of muscle activation on the elbow active ranges of motion. Methods During voluntary elbow pronation/supination and extension/flexion movements, kinematic and electromyographic measurements were collected from the involved upper limb of 15 children with spastic hemiplegic cerebral palsy (mean age = 8.7 years, standard deviation = 2.2) and the dominant upper limb of 15 age-matched children who are typically developing. Representative indicators of the muscle activation, such as the muscle co-activation, were extracted from the electromyographic measurements. Findings Muscle co-activation in the involved upper limb accounted for 78% and 59% of the explained variance of the supination and extension limited active ranges of motion respectively. The agonist and antagonist muscle activations were both longer in the involved upper limb. Interpretations This study succeeded in quantifying the impact of longer antagonist muscle activation on decreased elbow active ranges of motion in children with spastic hemiplegic cerebral palsy. Longer agonist muscle activation suggests that strengthening agonist muscles could increase the extension and supination ranges of motion, which constitutes a perspective of future clinical studies