Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype.

Chromatin remodeling is a complex process shaping the nucleosome landscape, thereby regulating the accessibility of transcription factors to regulatory regions of target genes and ultimately managing gene expression. The SWI/SNF (switch/sucrose nonfermentable) complex remodels the nucleosome landscape in an ATP-dependent manner and is divided into the two major subclasses Brahma-associated factor (BAF) and Polybromo Brahma-associated factor (PBAF) complex. Somatic mutations in subunits of the SWI/SNF complex have been associated with different cancers, while germline mutations have been associated with autism spectrum disorder and the neurodevelopmental disorders Coffin-Siris (CSS) and Nicolaides-Baraitser syndromes (NCBRS). CSS is characterized by intellectual disability (ID), coarsening of the face and hypoplasia or absence of the fifth finger- and/or toenails. So far, variants in five of the SWI/SNF subunit-encoding genes ARID1B, SMARCA4, SMARCB1, ARID1A, and SMARCE1 as well as variants in the transcription factor-encoding gene SOX11 have been identified in CSS-affected individuals. ARID2 is a member of the PBAF subcomplex, which until recently had not been linked to any neurodevelopmental phenotypes. In 2015, mutations in the ARID2 gene were associated with intellectual disability. In this study, we report on two individuals with private de novo ARID2 frameshift mutations. Both individuals present with a CSS-like phenotype including ID, coarsening of facial features, other recognizable facial dysmorphisms and hypoplasia of the fifth toenails. Hence, this study identifies mutations in the ARID2 gene as a novel and rare cause for a CSS-like phenotype and enlarges the list of CSS-like genes.

Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism.

The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.

Comprehensive review of the duplication 3q syndrome and report of a patient with Currarino syndrome and de novo duplication 3q26.32-q27.2.

Partial duplications of the long arm of chromosome 3, dup(3q), are a rare but well-described condition, sharing features of Cornelia de Lange syndrome. Around two thirds of cases are derived from unbalanced translocations, whereas pure dup(3q) have rarely been reported. Here, we provide an extensive review of the literature on dup(3q). This search revealed several patients with caudal malformations and anomalies, suggesting that caudal malformations or anomalies represent an inherent phenotypic feature of dup(3q). In this context, we report a patient with a pure de novo duplication 3q26.32-q27.2. The patient had the clinical diagnosis of Currarino syndrome (CS) (characterized by the triad of sacral anomalies, anorectal malformations and a presacral mass) and additional features, frequently detected in patients with a dup(3q). Mutations within the MNX1 gene were found to be causative in CS but no MNX1 mutation could be detected in our patient. Our comprehensive search for candidate genes located in the critical region of the duplication 3q syndrome, 3q26.3-q27, revealed a so far neglected phenotypic overlap of dup(3q) and the Pierpont syndrome, associated with a mutation of the TBL1XR1 gene on 3q26.32.

Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction.

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.

'Splitting versus lumping': Temple-Baraitser and Zimmermann-Laband Syndromes.

KCNH1 mutations have recently been described in six individuals with Temple-Baraitser syndrome (TMBTS) and six individuals with Zimmermann-Laband syndrome (ZLS). TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails. ZLS is characterized by facial dysmorphism including coarsening of the face and a large nose, gingival enlargement, ID, hypoplasia of terminal phalanges and nails and hypertrichosis. In this study, we present four additional unrelated individuals with de novo KCNH1 mutations from ID cohorts. We report on a novel recurrent pathogenic KCNH1 variant in three individuals and add a fourth individual with a previously TMBTS-associated KCNH1 variant. Neither TMBTS nor ZLS was suspected clinically. KCNH1 encodes a voltage-gated potassium channel, which is not only highly expressed in the central nervous system, but also seems to play an important role during development. Clinical evaluation of our mutation-positive individuals revealed that one of the main characteristics of TMBTS/ZLS, namely the pronounced nail hypoplasia of the great toes and thumbs, can be mild and develop over time. Clinical comparison of all published KCNH1 mutation-positive individuals revealed a similar facial but variable limb phenotype. KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes. In summary, we show that the phenotypic variability of individuals with KCNH1 mutations is more pronounced than previously expected, and we discuss whether KCNH1 mutations allow for "lumping" or for "splitting" of TMBTS and ZLS.

Effects of exercise on S-IGA and URS in postmenopausal women.

32 postmenopausal women were randomized to a 16-week home-based walking program or control group. Before and after the intervention, each subject completed a graded maximal treadmill test to establish VO(2)max and resting saliva was collected to determine levels of salivary immunoglobulin A. The 16-week walking program resulted in an increase in VO(2)max (+10.4%; p<0.01). Repeated measures ANOVA revealed a marked increase in the resting secretion rate of salivary immunoglobulin A (+37.4%; p<0.05) in the exercise group following training. Independent of study group, both before and after the intervention, the secretion rate of salivary immunoglobulin A ( - 32.3%) and saliva flow rate (- 29.3%) were reduced following acute maximal exercise (p<0.05). Weekly upper respiratory symptomatology logs revealed that the number of incidences of upper respiratory symptoms throughout the intervention period were the same and the duration per incidence (control: 5.3±1.5 days; exercise: 6.3±2.2 days) were similar between study groups. These findings in postmenopausal women support that the secretion rate of salivary immunoglobulin A and saliva flow rate are reduced immediately following maximal exercise. Moreover, a 16-week moderate intense walking program can increase the secretion of salivary immunoglobulin A without affecting upper respiratory symptomatology.

Effect of caffeine on LT, VT and HRVT.

UNLABELLED: Caffeine has many diverse physiological effects including central nervous system stimulation. Ventilatory threshold and a recently described heart rate variability threshold both have a relationship with autonomic control that could be altered by caffeine consumption. The purpose of this investigation was to determine the influence of caffeine on lactate, ventilatory, and heart rate variability thresholds during progressive exercise. Using a randomized placebo controlled, double-blind study design, 10 adults performed 2 graded maximal cycle ergometry tests with and without caffeine (5 mg·kg⁻¹). Respiratory gas exchange, blood lactate concentrations, and heart rate variability data were obtained at baseline and throughout exercise. RESULTS: At rest, caffeine (p<0.05) increased blood lactate, oxygen consumption, carbon dioxide production, and minute ventilation. For indices of heart rate variability at rest, caffeine increased (p<0.05) the coefficient of variation, while standard deviation, and mean successive difference displayed non-significant increases. During progressive exercise, minute ventilation volumes were higher in caffeine trials but no other parameters were significantly different compared to placebo tests. CONCLUSION: These data demonstrate the robustness of the lactate, ventilatory and heart rate variability thresholds when challenged by a physiological dose of caffeine.

Evaluating resistance to Bt toxin Cry1Ab by F2 screen in European populations of Ostrinia nubilalis (Lepidoptera: Crambidae).

The large-scale cultivation of transgenic crops producing Bacillus thuringiensis (Bt) toxins have already lead to the evolution of Bt resistance in some pest populations targeted by these crops. We used the F2 screening method for further estimating the frequency of resistance alleles of the European corn borer, Ostrinia nubilalis (Hübner) (Lepidoptera: Crambidae), to Bt maize, Zea mays L., producing the Cry1Ab toxin. In France, Germany, and Italy, 784, 455, and 80 lines of European corn borer were screened for resistance to Mon810 maize, respectively. In Slovakia, 26 lines were screened for resistance to the Cry1Ab toxin. The cost of F2 screen performed in the four countries varied from U.S. dollars 300 to dollars 1300 per line screened. The major difference in cost was mostly due to a severe loss of univoltine lines during the screen in Germany and Slovakia. In none of the screened lines did we detect alleles conferring resistance to Mon810 maize or to the Cry1Ab toxin. The frequency of resistance alleles were < 1.0 x 10(-3), < 1.6 x 10(-3), < 9.2 x 10(-3), and < 2.6 x 10(-2) in France, Germany, Italy, and Slovakia, with 95% probability, respectively. The average detection probability over all lines was approximately 90%. Making the assumption that European corn borer populations in these countries belong to the same genetic entity, the frequency of alleles conferring resistance to the Cry1Ab produced by the Mon810 maize in western and central Europe was 1.0 x 10(-4), with a 95% confidence interval of 0-3.0 x 10(-4).

[Paranoia and Asperger syndrome]. / Paranoia en het aspergersyndroom.

Paranoia in patients diagnosed with Asperger syndrome in adulthood is discussed and illustrated with the help of a case study. Impaired mentalisation, characteristic for Asperger disorder, influences the way an individual experiences life, making him more vulnerable for the development of delusional beliefs.

Mortality from diseases other than cancer following low doses of ionizing radiation: results from the 15-Country Study of nuclear industry workers.

BACKGROUND: Ionizing radiation at very high (radio-therapeutic) dose levels can cause diseases other than cancer, particularly heart diseases. There is increasing evidence that doses of the order of a few sievert (Sv) may also increase the risk of non-cancer diseases. It is not known, however, whether such effects also occur following the lower doses and dose rates of public health concern. METHODS: We used data from an international (15-country) nuclear workers cohort study to evaluate whether mortality from diseases other than cancer is related to low doses of external ionizing radiation. Analyses included 275 312 workers with adequate information on socioeconomic status, over 4 million person-years of follow-up and an average cumulative radiation dose of 20.7 mSv; 11 255 workers had died of non-cancer diseases. RESULTS: The excess relative risk (ERR) per Sv was 0.24 [95% CI (confidence intervals) -0.23, 0.78] for mortality from all non-cancer diseases and 0.09 (95% CI -0.43, 0.70) for circulatory diseases. Higher risk estimates were observed for mortality from respiratory and digestive diseases, but confidence intervals included zero. Increased risks were observed among the younger workers (attained age <50 years, identified post hoc) for all groupings of non-cancer causes of death, including external causes. It is unclear therefore whether these findings reflect real effects of radiation, random variation or residual confounding. CONCLUSIONS: The most informative low-dose radiation study to date provides little evidence for a relationship between mortality from non-malignant diseases and radiation dose. However, we cannot rule out risks per unit dose of the same order of magnitude as found in studies at higher doses.

The 15-Country Collaborative Study of Cancer Risk Among Radiation Workers in the Nuclear Industry: design, epidemiological methods and descriptive results.

Radiation protection standards are based mainly on risk estimates from studies of atomic bomb survivors in Japan. The validity of extrapolations from the relatively high-dose acute exposures in this population to the low-dose, protracted or fractionated environmental and occupational exposures of primary public health concern has long been the subject of controversy. A collaborative retrospective cohort study was conducted to provide direct estimates of cancer risk after low-dose protracted exposures. The study included nearly 600,000 workers employed in 154 facilities in 15 countries. This paper describes the design, methods and results of descriptive analyses of the study. The main analyses included 407,391 nuclear industry workers employed for at least 1 year in a participating facility who were monitored individually for external radiation exposure and whose doses resulted predominantly from exposure to higher-energy photon radiation. The total duration of follow-up was 5,192,710 person-years. There were 24,158 deaths from all causes, including 6,734 deaths from cancer. The total collective dose was 7,892 Sv. The overall average cumulative recorded dose was 19.4 mSv. A strong healthy worker effect was observed in most countries. This study provides the largest body of direct evidence to date on the effects of low-dose protracted exposures to external photon radiation.

The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: estimates of radiation-related cancer risks.

A 15-Country collaborative cohort study was conducted to provide direct estimates of cancer risk following protracted low doses of ionizing radiation. Analyses included 407,391 nuclear industry workers monitored individually for external radiation and 5.2 million person-years of follow-up. A significant association was seen between radiation dose and all-cause mortality [excess relative risk (ERR) 0.42 per Sv, 90% CI 0.07, 0.79; 18,993 deaths]. This was mainly attributable to a dose-related increase in all cancer mortality (ERR/Sv 0.97, 90% CI 0.28, 1.77; 5233 deaths). Among 31 specific types of malignancies studied, a significant association was found for lung cancer (ERR/Sv 1.86, 90% CI 0.49, 3.63; 1457 deaths) and a borderline significant (P = 0.06) association for multiple myeloma (ERR/Sv 6.15, 90% CI <0, 20.6; 83 deaths) and ill-defined and secondary cancers (ERR/Sv 1.96, 90% CI -0.26, 5.90; 328 deaths). Stratification on duration of employment had a large effect on the ERR/Sv, reflecting a strong healthy worker survivor effect in these cohorts. This is the largest analytical epidemiological study of the effects of low-dose protracted exposures to ionizing radiation to date. Further studies will be important to better assess the role of tobacco and other occupational exposures in our risk estimates.

Radiation exposure and cause specific mortality among nuclear workers in Belgium (1969-1994).

Cause specific mortality was studied in nuclear workers from five nuclear facilities in Belgium and compared to the general population. For the 1969-1994 period, mortality in male nuclear workers is significantly lower for all causes of death and for all cancer deaths. The same conclusions are reached if one assumes a latency period of 20 y between the first irradiation and cancer induction. In female workers, mortality due to all causes and all cancer deaths is not different from that of the general population. Analysis of cause specific mortality was performed for male and female workers for three endpoints: specific cancer sites, cardiovascular and respiratory diseases. No significant increase in mortality was observed. In male workers, the influence of cumulative dose was also investigated using four dose levels: no significant correlation was found. Smoking habits may be a confounding factor in smoking related health conditions.

Identification of supernumerary der(20) chromosomes by FISH in three patients.

Small supernumerary marker chromosomes of 3 patients were characterized at the molecular cytogenetic level. Two ring chromosomes and one metacentric marker were shown to be distamycinA/DAPI-negative and did not possess satellite regions after conventional banding techniques. Fluorescence in situ hybridization (FISH) was performed and in all 3 cases the supernumerary markers were shown to be derived from chromosome 20. Phenotypes are described and discussed with respect to karyotypes. Two of the patients are developmentally and/or phenotypically normal. The first patient has a ring chromosome, containing a small amount of euchromatic material; the second patient is the carrier of a small, metacentric and most probably heterochromatic marker. Patient 3 has physical anomalies, including a congenital heart defect and delayed motor development, but is intellectually almost normal. His marker chromosome is a ring containing a small amount of euchromatic material.

Delineation of supernumerary marker chromosomes in 38 patients.

We present cytogenetic and clinical data on 38 patients with supernumerary marker chromosomes (SMCs). SMCs were characterized using a strategy combining classical banding techniques and molecular cytogenetic studies. Cases were ascertained prenatally, postnatally, and after fetal death. In 26 patients (68%), the SMC originated entirely from acrocentric chromosomes. Among these, most patients carried a der(15). In 11 patients (29%), they were of nonacrocentric origin, including 9 autosomal and 2 gonosomal marker chromosomes. In 1 patient the SMC was of partially acrocentric origin. Patients with small derivatives of chromosome 15 [der(15)] had a normal phenotype. Those with a larger der(15) showed phenotypical abnormalities. Patients with supernumerary marker chromosomes derived from chromosomes 13 or 21, and 14 appeared to have a low risk of abnormalities. Out of this group only 1 patient who carried an additional r(21) had physical anomalies. Patients with an SMC originating from chromosome 22 showed physical abnormalities in 2 out of 6 cases. Supernumerary marker chromosomes identified as i(9p), i(12p), and der(18) were all associated with an abnormal phenotype. Two of the derivatives of chromosome 20 analyzed were correlated with a normal phenotype, while the carrier of the third one showed physical anomalies and motor retardation. Of 2 patients with an extra der(X), 1 was normal and 1 showed an abnormal phenotype.

The new voltage gated potassium channel KCNQ5 and neonatal convulsions.

In 1998, mutations in the voltage gated potassium channel gene KCNQ2 were found to be the main cause underlying the autosomal dominant inherited syndrome of benign familial neonatal convulsions (BFNC). In one BFNC family a mutation was found in an homologous gene, KCNQ3. We have now identified another brain-expressed member of this ion channel subfamily, KCNQ5, which maps to chromosome 6q14. On the genomic level KCNQ5 is composed of 14 exons, which are coding for 897 amino acid residues. Mutation analysis made KCNQ5 unlikely as a candidate gene for benign neonatal convulsions in patients with a positive family history for neonatal or early infantile seizures, but without mutations in the KCNQ2 or KCNQ3 genes.

Relative biological effectiveness of neutrons for cancer induction and other late effects: a review of radiobiological data.

The risk of secondary cancer induction after a therapeutic irradiation with conventional photon beams is well recognised and documented. However, in general, it is totally overwhelmed by the benefit of the treatment. The same is true to a large extent for the combinations of radiation and drug therapy. After fast neutron therapy, the risk of secondary cancer induction is greater than after photon therapy. This can be expected from the whole set of radiobiological data, accumulated so far, which shows systematically a greater relative biological effectiveness (RBE) for neutrons for all the biological systems which have been investigated. Furthermore, the neutron RBE increases with decreasing dose and there is extensive evidence that neutron RBE is greater for cancer induction and for other late effects relevant in radiation protection than for cell killing at high doses as used in therapy. Almost no reliable human epidemiological data are available so far, and the aim of this work is to derive the best risks estimate for cancer induction after neutron irradiation and in particular fast neutron therapy. Animal data on RBE for tumour induction are analysed. In addition, other biological effects are reviewed, such as life shortening, malignant cell transformation in vitro, chromosome aberrations, genetic effects. These effects can be related, directly or indirectly, to cancer induction to the extent that they express a "genomic" lesion. Since neutron RBE depends on the energy spectrum, the radiation quality has to be carefully specified. Therefore, the microdosimetric spectra are reported each time they are available. Lastly, since heavy-ion beam therapy is being developed at several centres worldwide, the available data on RBE at low doses are reviewed. It can be concluded from this review that the risk of induction of a secondary cancer after fast neutron therapy should not be greater than 10-20 times the risk after photon beam therapy. For heavy ions, and in particular for carbon ions, the risk estimate should be divided by a factor of about 3 due to the reduced integral dose. The risk has to be balanced against the expected improvement in cure rate when the indication for high-LET therapy has been correctly evaluated in well-selected patient groups.

No ergogenic effects of ginseng (Panax ginseng C.A. Meyer) during graded maximal aerobic exercise.

OBJECTIVE: To assess the effects of chronic supplementation with two different dosages of Panax ginseng C.A. Meyer on physiologic and psychological responses during graded maximal aerobic exercise. DESIGN: Randomized, double-blind, placebo-controlled trial. SUBJECTS: Thirty-six healthy men consuming an otherwise supplement-free diet who maintained their usual activity level. INTERVENTION: A standardized P ginseng C.A. Meyer concentrate (G115) was added to the normal diet of study participants at a dosage level of either 200 or 400 mg/day, where 100 mg of the preparation is equivalent to 500 mg P gingseng root. MAIN OUTCOME MEASURES: Submaximal and maximal aerobic exercise responses before and after an 8-week trial intervention. STATISTICAL ANALYSES PERFORMED: Analysis of variance. RESULTS: Thirty-one subjects completed the study. Supplementation with ginseng had no effect on the following physiologic and psychological parameters: oxygen consumption (mL/kg per minute), respiratory exchange ratio, minute ventilation (L/min), blood lactic acid concentration (mmol/L), heart rate (beats/min), and perceived exertion (P > .05). CONCLUSIONS: Our data in healthy men do not offer support for claims that P ginseng C.A. Meyer is an ergogenic aid to improve submaximal and maximal aerobic exercise performance.

Ginseng does not enhance psychological well-being in healthy, young adults: results of a double-blind, placebo-controlled, randomized clinical trial.

OBJECTIVE: Ginseng is a popular, commercially available dietary supplement that is purported to have a number of psychological benefits. The purpose of this study was to examine these claims, with specific reference to ginseng's effects on affect and mood. DESIGN: Prospective, double-blind, placebo-controlled, randomized clinical trial. PARTICIPANTS/SETTING: Eighty-three adults (40 women, 43 men) participated in this study (mean age = 25.7 year). Participants were recruited from within a university community and at area health clubs. INTERVENTION: Participants were randomly assigned to one of three experimental conditions: placebo (lactose), 200 mg ginseng, or 400 mg ginseng. The ginseng preparation used in this study consisted of the Panax ginseng C A Meyer concentrate G115 in capsular format. Each participant was given a 60-day allotment of their respective supplement along with written instructions about the proper intake and storage of the capsules during the 8-week study period. MAIN OUTCOME MEASURES: Positive affect, negative affect, and total mood disturbance. Measures were obtained pre- and post-intervention. STATISTICAL ANALYSES PERFORMED: Repeated measures multivariate analysis of variance was used. Because there were three dependent variables, and in an effort to minimize the experimentwise-error rate, alpha was adjusted using the Bonferroni technique (i.e., P < .05/3 = P < .016). RESULTS: Ginseng supplementation had no effect on positive affect, negative affect, or total mood disturbance (all P > .016). CONCLUSION: The present findings do not support claims that chronic ginseng supplementation--at either its clinically recommended level or at twice that level--enhances affect or mood in healthy young adults.