Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6–1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin

Synaptic Transmission from Horizontal Cells to Cones Is Impaired by Loss of Connexin Hemichannels

In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina

A cognitive decline precedes the onset of psychosis in patients with the 22q11.2 deletion syndrome

Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk for developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities, starting at a young age

Physical activity patterns in older men and women in Germany: a cross-sectional study

Data on physical activity in older adults in Germany is scarce. The aim of this study was to analyze physical activity patterns and to explore factors associated with physical activity in different domains, i.e. sporting activities (SA) and domestic activities (DA), in older men and women.; As part of the 7-year follow-up telephone interviews of the getABI cohort (community-dwelling older adults in Germany), the PRISCUS-PAQ was used to survey participants about their everyday physical activity patterns. Time per week (hh:mm) spent in SA and DA (heavy housework, gardening) was analyzed for men and women. Multivariate logistic regression analyses were performed in order to assess the odds of participating in SA and DA for at least 2.5 hours/week in association with sociodemographic factors, a broad range of physical health-related factors and interview date (season of the year).; A total of 1,610 primary health care patients (51.6% women) with a median age of 77 (range 72-93) years were included in the analyses. Men engaged in SA more often than women (01:45 vs. 01:10), whereas women did more DA per week than men (04:00 vs. 03:00).Being interviewed in spring or summer was associated with increased performance of DA in both sexes. Participation in these activities was reduced in more highly educated men and women. Living alone increased the odds of sports participation in women, but not in men. Most physical health-related factors were only selectively associated with either SA or DA, in men or women, respectively. The need for a walking aid was the only factor that consistently lowered the odds of being active in both activity domains and sexes.; This exploratory study delivers reliable and relevant data on the participation in and correlates of sporting and domestic activities of community-dwelling older adults for whom there had previously been only limited information at a population level in Germany. Findings are discussed and implications for epidemiological research and health promotion practice are provided

Correlates of sport participation among community-dwelling elderly people in Germany: a cross-sectional study

The aims of this study were (1) to analyze the sport participation in a cohort of community-dwelling elderly people in Germany and (2) to evaluate associations between sport participation, sociodemographic factors, cardiovascular risk factors, and health status. In a monitored prospective cohort study (getABI), 6,880 unselected patients ≥65 years have been followed up by 344 general practitioners beginning in 2001. As part of the 5-year follow-up telephone interview, a sample of 1,376 participants was interviewed on sport participation. The association between participation in at least one sporting activity (“sporty” yes/no) during the past week (cycling) or month (other sports) and the following parameters was analyzed by logistic regression: age, sex, immigration background, education, waist circumference, smoking, self-reported health, history of vascular events, diabetes mellitus, lipometabolic disorder, and arterial hypertension. Analysis of activities (n = 1,304; median age 76 (70–94) years; 55.1% women) showed that 27.6% of participants rode a bicycle during the previous week. During the previous month, 24.9% of participants did gymnastics or strength training, and 16.5% swam. Of all participants, 53.8% were sporty. Multivariate analysis revealed several independent factors to be associated with being sporty (p < 0.05): younger age, male sex, higher education, nonsmoking, better self-reported health, and not being diagnosed with diabetes. Immigration background, waist circumference, history of vascular events, lipometabolic disorder, and hypertension did not show a statistically significant association (p ≥ 0.05) with sport participation. Summing up, the most frequently performed sporting activities were cycling, gymnastics or strength training, and swimming. Sport participation was associated with, for example, age and sex

Explaining the variable penetrance of CNVs : Parental intelligence modulates expression of intellectual impairment caused by the 22q11.2 deletion

The role of rare genetic variants, in particular copy number variants (CNVs), in the etiology of neurodevelopmental disorders is becoming increasingly clear. While the list of these disorder-related CNVs continues to lengthen, it has also become clear that in nearly all genetic variants the proportion of carriers who express the associated phenotype is far from 100%. To understand this variable penetrance of CNVs it is important to realize that even the largest CNVs represent only a tiny fraction of the entire genome. Therefore, part of the mechanism underlying the variable penetrance of CNVs is likely the modulatory impact of the rest of the genome. In the present study we used the 22q11DS as a model to examine whether the observed penetrance of intellectual impairment-one of the main phenotypes associated with 22q11DS-is modulated by the intellectual level of their parents, for which we used the parents' highest level of education as a proxy. Our results, based on data observed in 171 children with 22q11DS in the age range of 5-15 years, showed a significant association between estimated parental cognitive level and intelligence in offspring (full scale, verbal and performance IQ), with the largest effect size for verbal IQ. These results suggest that possible mechanisms involved in the variable penetrance observed in CNVs include the impact of genetic background and/or environmental influences

Explaining the variable penetrance of CNVs : Parental intelligence modulates expression of intellectual impairment caused by the 22q11.2 deletion

The role of rare genetic variants, in particular copy number variants (CNVs), in the etiology of neurodevelopmental disorders is becoming increasingly clear. While the list of these disorder-related CNVs continues to lengthen, it has also become clear that in nearly all genetic variants the proportion of carriers who express the associated phenotype is far from 100%. To understand this variable penetrance of CNVs it is important to realize that even the largest CNVs represent only a tiny fraction of the entire genome. Therefore, part of the mechanism underlying the variable penetrance of CNVs is likely the modulatory impact of the rest of the genome. In the present study we used the 22q11DS as a model to examine whether the observed penetrance of intellectual impairment-one of the main phenotypes associated with 22q11DS-is modulated by the intellectual level of their parents, for which we used the parents' highest level of education as a proxy. Our results, based on data observed in 171 children with 22q11DS in the age range of 5-15 years, showed a significant association between estimated parental cognitive level and intelligence in offspring (full scale, verbal and performance IQ), with the largest effect size for verbal IQ. These results suggest that possible mechanisms involved in the variable penetrance observed in CNVs include the impact of genetic background and/or environmental influences