Chromosomal insertions are genomic rearrangements with a chromosome segment inserted into a non-homologous chromosome or a non-adjacent locus on the same chromosome or the other homologue, ...constituting ~2% of nonrecurrent copy-number gains. Little is known about the molecular mechanisms of their formation. We identified 16 individuals with complex insertions among 56,000 individuals tested at Baylor Genetics using clinical array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). Custom high-density aCGH was performed on 10 individuals with available DNA, and breakpoint junctions were fine-mapped at nucleotide resolution by long-range PCR and DNA sequencing in 6 individuals to glean insights into potential mechanisms of formation. We observed microhomologies and templated insertions at the breakpoint junctions, resembling the breakpoint junction signatures found in complex genomic rearrangements generated by replication-based mechanism(s) with iterative template switches. In addition, we analyzed 5 families with apparently balanced insertion in one parent detected by FISH analysis and found that 3 parents had additional small copy-number variants (CNVs) at one or both sides of the inserting fragments as well as at the inserted sites. We propose that replicative repair can result in interchromosomal complex insertions generated through chromothripsis-like chromoanasynthesis involving two or three chromosomes, and cause a significant fraction of apparently balanced insertions harboring small flanking CNVs.
Cas13 nucleases are a class of programmable RNA-targeting CRISPR effector proteins that are capable of silencing target gene expression in mammalian cells. Here, we demonstrate that RfxCas13d, a ...Cas13 ortholog with favorable characteristics to other family members, can be delivered to the mouse spinal cord and brain to silence neurodegeneration-associated genes. Intrathecally delivering an adeno-associated virus vector encoding an RfxCas13d variant programmed to target superoxide dismutase 1 (SOD1), a protein whose mutation can cause amyotrophic lateral sclerosis, reduced SOD1 mRNA and protein in the spinal cord by >50% and improved outcomes in a mouse model of the disorder. We further show that intrastriatally delivering an RfxCas13d variant programmed to target huntingtin (HTT), a protein whose mutation is causative for Huntington’s disease, led to a ~50% reduction in HTT protein in the mouse brain. Our results establish RfxCas13d as a versatile platform for knocking down gene expression in the nervous system.
Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are ...extremely rare, indicating high intolerance of haploinsufficiency.
Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24.
We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease.
These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.
Copper (Cu) is a bioelement essential for a myriad of enzymatic reactions, which when present in high concentration leads to cytotoxicity. Whereas Cu toxicity is usually assumed to originate from the ...metal's ability to enhance lipid peroxidation, the role of oxidative stress has remained uncertain since no antioxidant therapy has ever been effective. Here we show that Cu overload induces cell death independently of the metal's ability to oxidize the intracellular milieu. In fact, cells neither lose control of their thiol homeostasis until briefly before the onset of cell death, nor trigger a consistent antioxidant response. As expected, glutathione (GSH) protects the cell from Cu-mediated cytotoxicity but, surprisingly, fully independent of its reactive thiol. Moreover, the oxidation state of extracellular Cu is irrelevant as cells accumulate the metal as cuprous ions. We provide evidence that cell death is driven by the interaction of cuprous ions with proteins which impairs protein folding and promotes aggregation. Consequently, cells mostly react to Cu by mounting a heat shock response and trying to restore protein homeostasis. The protective role of GSH is based on the binding of cuprous ions, thus preventing the metal interaction with proteins. Due to the high intracellular content of GSH, it is depleted near the Cu entry site, and hence Cu can interact with proteins and cause aggregation and cytotoxicity immediately below the plasma membrane.
Deep brain stimulation (DBS) has been proposed as an alternative to ablative neurosurgery for severe treatment-resistant Obsessive-Compulsive Disorder (OCD), although with partially discrepant ...results probably related to differences in anatomical targetting and stimulation conditions. We sought to determine the efficacy and tolerability of DBS in OCD and the existence of clinical predictors of response using meta-analysis.
We searched the literature on DBS for OCD from 1999 through January 2014 using PubMed/MEDLINE and PsycINFO. We performed fixed and random-effect meta-analysis with score changes (pre-post DBS) on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) as the primary-outcome measure, and the number of responders to treatment, quality of life and acceptability as secondary measures.
Thirty-one studies involving 116 subjects were identified. Eighty-three subjects were implanted in striatal areas--anterior limb of the internal capsule, ventral capsule and ventral striatum, nucleus accumbens and ventral caudate--27 in the subthalamic nucleus and six in the inferior thalamic peduncle. Global percentage of Y-BOCS reduction was estimated at 45.1% and global percentage of responders at 60.0%. Better response was associated with older age at OCD onset and presence of sexual/religious obsessions and compulsions. No significant differences were detected in efficacy between targets. Five patients dropped out, but adverse effects were generally reported as mild, transient and reversible.
Our analysis confirms that DBS constitutes a valid alternative to lesional surgery for severe, therapy-refractory OCD patients. Well-controlled, randomized studies with larger samples are needed to establish the optimal targeting and stimulation conditions and to extend the analysis of clinical predictors of outcome.
Due to the increasing evidence of shared vulnerabilities between addictive behaviors and excessive food intake, the concept of food addiction in specific clinical populations has become a topic of ...scientific interest. The aim of this study was to validate the Yale Food Addiction Scale (YFAS) 2.0 in a Spanish sample. We also sought to explore food addiction and its clinical correlates in eating disorder (ED) and gambling disorder (GD) patients.
The sample included 301 clinical cases (135 ED and 166 GD), diagnosed according to DSM-5 criteria, and 152 healthy controls (HC) recruited from the general population.
Food addiction was more prevalent in patients with ED, than in patients with GD and HC (77.8, 7.8, and 3.3%, respectively). Food addiction severity was associated with higher BMI, psychopathology and specific personality traits, such as higher harm avoidance, and lower self-directedness. The psychometrical properties of the Spanish version of the YFAS 2.0 were excellent with good convergent validity. Moreover, it obtained good accuracy in discriminating between diagnostic subtypes.
Our results provide empirical support for the use of the Spanish YFAS 2.0 as a reliable and valid tool to assess food addiction among several clinical populations (namely ED and GD). The prevalence of food addiction is heterogeneous between disorders. Common risk factors such as high levels of psychopathology and low self-directedness appear to be present in individuals with food addiction.
A 12-week, double-blind, parallel, multi-center randomized controlled trial in 316 adult patients with major depressive disorder (MDD) was conducted to evaluate the effectiveness of pharmacogenetic ...(PGx) testing for drug therapy guidance.
Patients with a CGI-S ≥ 4 and requiring antidepressant medication de novo or changes in their medication regime were recruited at 18 Spanish public hospitals, genotyped with a commercial PGx panel (Neuropharmagen®), and randomized to PGx-guided treatment (n = 155) or treatment as usual (TAU, control group, n = 161), using a computer-generated random list that locked or unlocked psychiatrist access to the results of the PGx panel depending on group allocation. The primary endpoint was the proportion of patients achieving a sustained response (Patient Global Impression of Improvement, PGI-I ≤ 2) within the 12-week follow-up. Patients and interviewers collecting the PGI-I ratings were blinded to group allocation. Between-group differences were evaluated using χ2-test or t-test, as per data type.
Two hundred eighty patients were available for analysis at the end of the 12-week follow-up (PGx n = 136, TAU n = 144). A difference in sustained response within the study period (primary outcome) was not observed (38.5% vs 34.4%, p = 0.4735; OR = 1.19 95%CI 0.74-1.92), but the PGx-guided treatment group had a higher responder rate compared to TAU at 12 weeks (47.8% vs 36.1%, p = 0.0476; OR = 1.62 95%CI 1.00-2.61), and this difference increased after removing subjects in the PGx-guided group when clinicians explicitly reported not to follow the test recommendations (51.3% vs 36.1%, p = 0.0135; OR = 1.86 95%CI 1.13-3.05). Effects were more consistent in patients with 1-3 failed drug trials. In subjects reporting side effects burden at baseline, odds of achieving a better tolerability (Frequency, Intensity and Burden of Side Effects Rating Burden subscore ≤2) were higher in the PGx-guided group than in controls at 6 weeks and maintained at 12 weeks (68.5% vs 51.4%, p = 0.0260; OR = 2.06 95%CI 1.09-3.89).
PGx-guided treatment resulted in significant improvement of MDD patient's response at 12 weeks, dependent on the number of previously failed medication trials, but not on sustained response during the study period. Burden of side effects was also significantly reduced.
European Clinical Trials Database 2013-002228-18 , registration date September 16, 2013; ClinicalTrials.gov NCT02529462 , retrospectively registered: August 19, 2015.
Sensory factors may play an important role in the determination of appetite and food choices. Also, some adipokines may alter or predict the perception and pleasantness of specific odors. We aimed to ...analyze differences in smell-taste capacity between females with different weights and relate them with fat and fat-free mass, visceral fat, and several adipokines.
179 females with different weights (from low weight to morbid obesity) were studied. We analyzed the relation between fat, fat-free mass, visceral fat (indirectly estimated by bioelectrical impedance analysis with visceral fat rating (VFR)), leptin, adiponectin and visfatin. The smell and taste assessments were performed through the "Sniffin' Sticks" and "Taste Strips" respectively.
We found a lower score in the measurement of smell (TDI-score (Threshold, Discrimination and Identification)) in obese subjects. All the olfactory functions measured, such as threshold, discrimination, identification and the TDI-score, correlated negatively with age, body mass index (BMI), leptin, fat mass, fat-free mass and VFR. In a multiple linear regression model, VFR mainly predicted the TDI-score. With regard to the taste function measurements, the normal weight subjects showed a higher score of taste functions. However a tendency to decrease was observed in the groups with greater or lesser BMI. In a multiple linear regression model VFR and age mainly predicted the total taste scores.
We show for the first time that a reverse relationship exists between visceral fat and sensory signals, such as smell and taste, across a population with different body weight conditions.
Gambling-related crimes are known to be associated with gambling disorder (GD). Due to a lack of consensus in the scientific community regarding the relevance of this diagnostic criterion, it was ...removed from the DSM-5. The primary aim of this study was to investigate through structural equation modeling (SEM) whether higher GD severity in treatment-seeking GD patients with a criminal record is mediated through the illegal acts criterion itself, or whether it can be better explained by other related clinical factors.
An initial sample of 2,081 patients seeking treatment for gambling problems was included in the sample. SEM was used to evaluate the mediational role of the illegal acts criterion between the sex, age and personality traits, gambling severity, and comorbid depression levels. Comparisons between patients with coinciding and divergent DSM criterion for GD diagnosis were carried out.
Illegal acts mediated the relationship between personality traits and GD severity: younger age, high levels of novelty seeking, and low levels of self-transcendence increased the risk of endorsing the illegal acts criterion. No differences between coincident-divergent groups in terms of DSM-IV and DSM-5 diagnosis were found with regards to sex (
= 0.878), education level (
= 0.387), or civil status (
= 0.792).
The results obtained in the present study offer new insights into the utility of using a history of illegal acts, their different personality characteristics, and psychopathology to categorize GD patients. Our findings suggest that patients who engage in criminal behavior may require a more comprehensive intervention.
Studies examining gambling preferences have identified the importance of the type of gambling practiced on distinct individual profiles. The objectives were to compare clinical, psychopathological ...and personality variables between two different groups of individuals with a gambling disorder (strategic and non-strategic gamblers) and to evaluate the statistical prediction capacity of these preferences with respect to the severity of the disorder.
A total sample of 2010 treatment-seeking patients with a gambling disorder participated in this stand-alone study. All were recruited from a single Pathological Gambling Unit in Spain (1709 strategic and 301 non-strategic gamblers). The design of the study was cross-sectional and data were collected at the start of treatment. Data was analysed using logistic regression for binary outcomes and analysis of variance (ANOVA) for quantitative responses.
There were significant differences in several socio-demographic and clinical variables, as well as in personality traits (novelty seeking and cooperativeness). Multiple regression analysis showed harm avoidance and self-directedness were the main predictors of gambling severity and psychopathology, while age at assessment and age of onset of gambling behaviour were predictive of gambling severity. Strategic gambling (as opposed to non-strategic) was significantly associated with clinical outcomes, but the effect size of the relationships was small.
It is possible to identify distinct phenotypes depending on the preference of gambling. While these phenotypes differ in relation to the severity of the gambling disorder, psychopathology and personality traits, they can be useful from a clinical and therapeutic perspective in enabling risk factors to be identified and prevention programs targeting specific individual profiles to be developed.
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