Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.

Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 (methyl-CpG-binding domain protein 5) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of this locus on human psychopathology has not been fully explored. To characterize the structural variation landscape of MBD5 disruptions and the associated human psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed that the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5'-untranslated region, confirming the critical impact of non-coding sequence at this locus. We identified heterogeneous, multisystem pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, including the novel finding of anxiety and bipolar disorder in multiple patients. Importantly, one of the unique features of the oldest known patient was behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study demonstrates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also indicates that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression.

Towards an evidence-based process for the clinical interpretation of copy number variation.

The evidence-based review (EBR) process has been widely used to develop standards for medical decision-making and to explore complex clinical questions. This approach can be applied to genetic tests, such as chromosomal microarrays, in order to assist in the clinical interpretation of certain copy number variants (CNVs), particularly those that are rare, and guide array design for optimal clinical utility. To address these issues, the International Standards for Cytogenomic Arrays Consortium has established an EBR Work Group charged with building a framework to systematically assess the potential clinical relevance of CNVs throughout the genome. This group has developed a rating system enumerating the evidence supporting or refuting dosage sensitivity for individual genes and regions that considers the following criteria: number of causative mutations reported; patterns of inheritance; consistency of phenotype; evidence from large-scale case-control studies; mutational mechanisms; data from public genome variation databases; and expert consensus opinion. The system is designed to be dynamic in nature, with regions being reevaluated periodically to incorporate emerging evidence. The evidence collected will be displayed within a publically available database, and can be used in part to inform clinical laboratory CNV interpretations as well as to guide array design.

Meiotic recombination involving heterozygous large insertions in Saccharomyces cerevisiae: formation and repair of large, unpaired DNA loops.

Meiotic recombination in Saccharomyces cerevisiae involves the formation of heteroduplexes, duplexes containing DNA strands derived from two different homologues. If the two strands of DNA differ by an insertion or deletion, the heteroduplex will contain an unpaired DNA loop. We found that unpaired loops as large as 5.6 kb can be accommodated within a heteroduplex. Repair of these loops involved the nucleotide excision repair (NER) enzymes Rad1p and Rad10p and the mismatch repair (MMR) proteins Msh2p and Msh3p, but not several other NER (Rad2p and Rad14p) and MMR (Msh4p, Msh6p, Mlh1p, Pms1p, Mlh2p, Mlh3p) proteins. Heteroduplexes were also formed with DNA strands derived from alleles containing two different large insertions, creating a large "bubble"; repair of this substrate was dependent on Rad1p. Although meiotic recombination events in yeast are initiated by double-strand DNA breaks (DSBs), we showed that DSBs occurring within heterozygous insertions do not stimulate interhomologue recombination.

Effects of electrically-stimulated exercise and passive motion on echocardiographically-derived wall motion and cardiodynamic function in tetraplegic persons.

The purposes of the study were (1) to characterize left ventricular wall motion, and the cardiodynamic and metabolic responses during electrical stimulation cycle ergometry (ESCE) exercise in tetraplegic people; (2) to test whether these responses linger into the post-exercise recovery period; and (3) to test whether they differ from those imposed by lower extremity continuous passive motion (CPM). Subjects were six tetraplegic males aged 25.8 +/- 3.1 (mean +/- SD) years with spinal cord injuries of 6.7 +/- 3.5 years' duration at the C5 and C6 levels (Frankel classifications A and B). On randomized non-consecutive days, subjects underwent either 30 min of steady-state exercise using transcutaneous electrically-stimulated contractions of bilateral quadriceps, hamstring, and gluteus muscle groups, or 30 min of continuous passive motion at 50 rpm. Data were taken at rest, min 15 and 30 of treatment, and min 5, 15, and 30 post-treatment. Stroke volume (SV) was measured echocardiographically as the product of the left ventricular outflow tract area and the integrated area under the left ventricular outflow tract flow-velocity curve acquired by doppler ultrasound. This value was multiplied by heart rate (HR) to determine the cardiac output (CO). Oxygen consumption (VO2) was monitored spirometrically, with arteriovenous oxygen difference (a-vO2DIFF) computed algebraically. Data were analyzed using repeated measures within-subjects design anaysis of variance, with significance accepted at the 0.05 level. Results showed five subjects had small hyperkinetic ventricles at rest that became more dynamic during ESCE than CPM. Though no systolic dysfunction was noted, all but one subject exhibited some degree of septal hypokinesis at rest and during exercise, possibly indicative of left ventricular noncompliance. Significant effects of condition (ESCE vs CPM), trial (measurement time point), and their interaction, were observed for CO (P < 0.05, 0.01, and 0.0001, respectively), HR (P < 0.0001, 0.05 and 0.005, respectively), and VO2 (P < 0.001, 0.05 and 0.005, respectively). A significant trial and condition by trial interaction was found for a-vO2DIFF (P < 0.05 and 0.0001, respectively). No effects for condition, trial or their interaction were found for SV or BPDIAS. Electrical stimulation cycle ergometry-treated subjects achieved peak VO2 of 712 +/- 300 ml min-1, 2.63 times baseline, with 56% elevation of a-vO2DIFF. Cardiac output increased from 3.5 +/- 1.51 min-1 to 6.0 +/- 2.11 min-1, an elevation solely attributable to a 57% increase in HR. Thus, both CO and a-vO2DIFF accounted for elevated VO2 during ESCE.(ABSTRACT TRUNCATED AT 400 WORDS)

Holistic medicine and technology: a modern dialectic.

This is an attempt to present a comprehensive overview of two major trends in American medicine which suggests significant evolutionary biopsychosocial developments in the remaining decades of the 20th century. Comments have been confined to the U.S. because it is the geographical country of residence and practice of the authors, and because the U.S. appears to be the locus of two contemporaneous and seemingly antithetical popular movements: quantum leaps in the development and use of medical technology and a groundswell of interest and enthusiasm for health enhancement or wellness which advocates a natural approach to health and emphasizes the central role of the individual in the preservation of health and the prevention of illness. The dynamics of this modern dialectic in American medicine have generated important qualitative consequences in the nature of the doctor-patient relationship and the delivery of health care. They have also, it is submitted, generated the search for a new paradigm which will permit a workable equilibrium between the disparate imperatives of both movements. The delicate process of developing that equilibrium is made more difficult by the co-existence of a host of complex factors, many of which are inextricably interwoven with one or the other of these two major trends.(ABSTRACT TRUNCATED AT 250 WORDS)