Identification of a DNA methylation episignature for recurrent constellations of embryonic malformations.

The term "recurrent constellations of embryonic malformations" (RCEM) is used to describe a number of multiple malformation associations that affect three or more body structures. The causes of these disorders are currently unknown, and no diagnostic marker has been identified. Consequently, providing a definitive diagnosis in suspected individuals is challenging. In this study, genome-wide DNA methylation analysis was conducted on DNA samples obtained from the peripheral blood of 53 individuals with RCEM characterized by clinical features recognized as VACTERL and/or oculoauriculovertebral spectrum association. We identified a common DNA methylation episignature in 40 out of the 53 individuals. Subsequently, a sensitive and specific binary classifier was developed based on the DNA methylation episignature. This classifier can facilitate the use of RCEM episignature as a diagnostic biomarker in a clinical setting. The study also investigated the functional correlation of RCEM DNA methylation relative to other genetic disorders with known episignatures, highlighting the common genomic regulatory pathways involved in the pathophysiology of RCEM.

Genetic and environmental factors driving congenital solitary functioning kidney.

BACKGROUND: Congenital solitary functioning kidney (CSFK) is an anomaly predisposing to hypertension, albuminuria and chronic kidney disease. Its aetiology is complex and includes genetic and environmental factors. The role of gene-environment interactions (G×E), although relevant for other congenital anomalies, has not yet been investigated. Therefore, we performed a genome-wide G×E analysis with six preselected environmental factors to explore the role of these interactions in the aetiology of CSFK. METHODS: In the AGORA (Aetiologic research into Genetic and Occupational/environmental Risk factors for Anomalies in children) data- and biobank, genome-wide single-nucleotide variant (SNV) data and questionnaire data on prenatal exposure to environmental risk factors were available for 381 CSFK patients and 598 healthy controls. Using a two-step strategy, we first selected independent significant SNVs associated with one of the six environmental risk factors. These SNVs were subsequently tested in G×E analyses using logistic regression models, with Bonferroni-corrected P-value thresholds based on the number of SNVs selected in step one. RESULTS: In step one, 7-40 SNVs were selected per environmental factor, of which only rs3098698 reached statistical significance (P = .0016, Bonferroni-corrected threshold 0.0045) for interaction in step two. The interaction between maternal overweight and this SNV, which results in lower expression of the Arylsulfatase B (ARSB) gene, could be explained by lower insulin receptor activity in children heterozygous for rs3098698. Eight other G×E interactions had a P-value <.05, of which two were biologically plausible and warrant further study. CONCLUSIONS: Interactions between genetic and environmental factors may contribute to the aetiology of CSFK. To better determine their role, large studies combining data on genetic and environmental risk factors are warranted.

Environmental and parental risk factors for congenital solitary functioning kidney - a case-control study.

BACKGROUND: The etiology of congenital solitary functioning kidney (CSFK) is largely unknown but likely includes various risk factors. We performed a case-control study to compare exposure to environmental and parental risk factors during embryonic kidney development between children with CSFK and healthy controls. METHODS: We included 434 children with CSFK and 1302 healthy controls from the AGORA data- and biobank matched on year of birth. Exposure to potential risk factors was investigated using parental questionnaire data. Crude and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were estimated for each potential risk factor. Multiple imputation was used to deal with missing values. Confounders for each potential risk factor were selected using directed acyclic graphs. RESULTS: Maternal stress was newly identified as a risk factor for CSFK (aOR 2.1, 95% CI 1.2-3.5). Known associations with conception using in vitro fertilization/intracytoplasmic sperm injection (aOR 1.8, 95% CI 1.0-3.2), maternal infections during pregnancy (aOR 2.5, 95% CI 1.4-4.7), smoking during pregnancy (aOR 1.4, 95% CI 1.0-2.0), and parental CAKUT (aOR 6.6, 95% CI 2.9-15.1) were confirmed, but previous associations with diabetes and obesity could not be replicated. Folic acid supplement use and younger maternal age seemed to reduce the risk of CSFK (aORs 0.7, 95% CI 0.5-1.0, and 0.8, 95% CI 0.6-1.0, respectively). CONCLUSIONS: Environmental and parental risk factors are likely to be involved in the development of CSFK and future studies should combine genetic, environmental, and gene-environment interaction analyses. Women wanting to become pregnant should consider optimizing their health and lifestyle. A higher-resolution version of the Graphical abstract is available as Supplementary information.

Health-related quality of life in children with congenital vascular malformations.

A cross-sectional study was performed to evaluate health-related quality of life (HRQOL) in children with congenital vascular malformations (CVM) and to investigate factors associated with an impaired HRQOL. Children (2-17 years) with CVMs who visited the HECOVAN expertise center between 2016-2018 were included. The PedsQL 4.0 Generic Core Scales were used and a score ≥ 1.0 SD below the normative mean was defined as an impaired HRQOL. Factors associated with impairment were investigated using univariate and multivariate logistic regression analysis. The median overall HRQOL was 84.8/100 (n = 207; 41% boys, 59% girls; self-reported IQR 73.9-92.4 and parent-reported IQR 71.4-92.4). Patients aged 13-17 years reported significantly worse physical functioning than those aged 8-12 years (median 84.4, IQR 71.1-93.8 versus median 90.6, IQR 81.3-96.9; p = 0.02). Parents reported a significantly lower overall HRQOL than their children (median 80.4, IQR 70.7-90.8 versus median 85.9, IQR 76.1-92.4; p = 0.001). HRQOL was impaired in 25% of patients. Impairment occurred significantly more often in lower extremity CVMs (38%, p = 0.01) and multifocal CVMs (47%, p = 0.01) compared to CVMs in the head/neck region (13%). Other associated factors included invasive management (31% versus 14%; p = 0.01), age at first treatment ≤ 5 years (48% versus 25%; p = 0.02) and ongoing treatment (38% versus 18%; p = 0.004). After correction for other factors, significance remained for lower extremity CVMs and ongoing invasive treatment. CONCLUSIONS: Overall median HRQOL was reasonable and not significantly different from the norm sample. Parental ratings were significantly lower than their children's ratings. A quarter of the patients had an impaired HRQOL, which seemed to worsen with age. Independently associated factors included a lower extremity CVM and invasive management. WHAT IS KNOWN: • Congenital vascular malformations could affect health-related quality of life (HRQOL). • Studies on pediatric patients are limited and either very small or in combination with adult patient series. WHAT IS NEW: • This study raises awareness of an impaired HRQOL in 25% of pediatric patients with congenital vascular malformations. • Associated factors included a lower extremity CVM and invasive management.

Rectal atresia and rectal stenosis: the ARM-Net Consortium experience.

PURPOSE: To assess the number, characteristics, and functional short-, and midterm outcomes of patients with rectal atresia (RA) and stenosis (RS) in the ARM-Net registry. METHODS: Patients with RA/RS were retrieved from the ARM-Net registry. Patient characteristics, associated anomalies, surgical approach, and functional bowel outcomes at 1 and 5-year follow-up were assessed. RESULTS: The ARM-Net registry included 2619 patients, of whom 36 (1.3%) had RA/RS. Median age at follow-up was 7.0 years (IQR 2.3-9.0). Twenty-three patients (63.9%, RA n = 13, RS n = 10) had additional anomalies. PSARP was the most performed reconstructive surgery for both RA (n = 9) and RS (n = 6) patients. At 1-year follow-up, 11/24 patients with known data (45.8%, RA n = 5, RS n = 6) were constipated, of whom 9 required stool softeners and/or laxatives. At 5-year follow-up, 8/9 patients with known data (88.9%, RA n = 4, RS n = 4) were constipated, all requiring laxatives and/or enema. CONCLUSION: RA and RS are rare types of ARM, representing 1.3% of patients in the ARM-Net registry. Additional anomalies were present in majority of patients. Different surgical approaches were performed as reconstructive treatment, with constipation occurring in 46% and 89% of the patients at 1 and 5-year follow-up. However, accurate evaluation of long-term functional outcomes remains challenging.

The CABB dataset: A multimodal corpus of communicative interactions for behavioural and neural analyses.

We present a dataset of behavioural and fMRI observations acquired in the context of humans involved in multimodal referential communication. The dataset contains audio/video and motion-tracking recordings of face-to-face, task-based communicative interactions in Dutch, as well as behavioural and neural correlates of participants' representations of dialogue referents. Seventy-one pairs of unacquainted participants performed two interleaved interactional tasks in which they described and located 16 novel geometrical objects (i.e., Fribbles) yielding spontaneous interactions of about one hour. We share high-quality video (from three cameras), audio (from head-mounted microphones), and motion-tracking (Kinect) data, as well as speech transcripts of the interactions. Before and after engaging in the face-to-face communicative interactions, participants' individual representations of the 16 Fribbles were estimated. Behaviourally, participants provided a written description (one to three words) for each Fribble and positioned them along 29 independent conceptual dimensions (e.g., rounded, human, audible). Neurally, fMRI signal evoked by each Fribble was measured during a one-back working-memory task. To enable functional hyperalignment across participants, the dataset also includes fMRI measurements obtained during visual presentation of eight animated movies (35 min total). We present analyses for the various types of data demonstrating their quality and consistency with earlier research. Besides high-resolution multimodal interactional data, this dataset includes different correlates of communicative referents, obtained before and after face-to-face dialogue, allowing for novel investigations into the relation between communicative behaviours and the representational space shared by communicators. This unique combination of data can be used for research in neuroscience, psychology, linguistics, and beyond.

Rare Variants in BNC2 Are Implicated in Autosomal-Dominant Congenital Lower Urinary-Tract Obstruction.

Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853∗]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.

The broader phenotypic spectrum of congenital caudal abnormalities associated with mutations in the caudal type homeobox 2 gene.

The caudal type homeobox 2 (CDX2) gene encodes a developmental regulator involved in caudal body patterning. Only three pathogenic variants in human CDX2 have been described, in patients with persistent cloaca, sirenomelia and/or renal and anogenital malformations. We identified five patients with de novo or inherited pathogenic variants in CDX2 with clinical phenotypes that partially overlap with previous cases, that is, imperforate anus and renal, urogenital and limb abnormalities. However, additional clinical features were seen including vertebral agenesis and we describe considerable phenotypic variability, even in unrelated patients with the same recurrent p.(Arg237His) variant. We propose CDX2 variants as rare genetic cause for a multiple congenital anomaly syndrome that can include features of caudal regression syndrome and VACTERL. A causative role is further substantiated by the relationship between CDX2 and other proteins encoded by genes that were previously linked to caudal abnormalities in humans, for example, TBXT (sacral agenesis and other vertebral segmentation defects) and CDX1 (anorectal malformations). Our findings confirm the essential role of CDX2 in caudal morphogenesis and formation of cloacal derivatives in humans, which to date has only been well characterized in animals.

Naturalism, tractability and the adaptive toolbox.

Many compelling examples have recently been provided in which people can achieve impressive epistemic success, e.g. draw highly accurate inferences, by using simple heuristics and very little information. This is possible by taking advantage of the features of the environment. The examples suggest an easy and appealing naturalization of rationality: on the one hand, people clearly can apply simple heuristics, and on the other hand, they intuitively ought do so when this brings them high accuracy at little cost.. The 'ought-can' principle is satisfied, and rationality is meaningfully normative. We show, however, that this naturalization program is endangered by a computational wrinkle in the adaptation process taken to be responsible for this heuristics-based ('ecological') rationality: for the adaptation process to guarantee even minimal rationality, it requires astronomical computational resources, making the problem intractable. We consider various plausible auxiliary assumptions in attempt to remove this obstacle, and show that they do not succeed; intractability is a robust property of adaptation. We discuss the implications of our findings for the project of naturalizing rationality.

Spectrum of congenital anomalies among VACTERL cases: a EUROCAT population-based study.

BACKGROUND: The VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities) association is the non-random occurrence of at least three of these congenital anomalies: vertebral, anal, cardiac, tracheo-esophageal, renal, and limb anomalies. Diagnosing VACTERL patients is difficult, as many disorders have multiple features in common with VACTERL. The aims of this study were to clearly outline component features, describe the phenotypic spectrum among the largest group of VACTERL patients thus far reported, and to identify phenotypically similar subtypes. METHODS: A case-only study was performed assessing data on 501 cases recorded with VACTERL in the JRC-EUROCAT (Joint Research Centre-European Surveillance of Congenital Anomalies) central database (birth years: 1980-2015). We differentiated between major and minor VACTERL features and anomalies outside the VACTERL spectrum to create a clear definition of VACTERL. RESULTS: In total, 397 cases (79%) fulfilled our VACTERL diagnostic criteria. The most commonly observed major VACTERL features were anorectal malformations and esophageal atresia/tracheo-esophageal fistula (both occurring in 62% of VACTERL cases), followed by cardiac (57%), renal (51%), vertebral (33%), and limb anomalies (25%), in every possible combination. Three VACTERL subtypes were defined: STRICT-VACTERL, VACTERL-LIKE, and VACTERL-PLUS, based on severity and presence of additional congenital anomalies. CONCLUSION: The clearly defined VACTERL component features and the VACTERL subtypes introduced will improve both clinical practice and etiologic research.

Maternal hypertensive disorders and subtypes of hypospadias: A Dutch case-control study.

BACKGROUND: Hypospadias is a frequently occurring congenital anomaly in male infants, in which the opening of the urethra is located along the ventral side of the penis. Although various studies attempted to identify its causes, the aetiology of the majority of hypospadias cases remains poorly understood. Maternal hypertensive disorders are believed to be associated with hypospadias, but the results of previous studies are not consistent, especially for subtypes of hypospadias. OBJECTIVES: To investigate the associations between maternal hypertensive disorders, stratified by pharmacological treatment, and the occurrence of hypospadias divided into subtypes in a large population-based case-control study. METHODS: We included 887 hypospadias cases and 1005 male controls from the AGORA data- and biobank. Cases and controls were born in the periods 1975-2016 and 1990-2011, respectively. All data were collected in the period 2004-2018. Maternal questionnaires were used to obtain information on hypertensive disorders during pregnancy, antihypertensive medication treatment, and potential confounders. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for the associations between hypertensive disorders and hypospadias were estimated using logistic regression. RESULTS: Hypertensive disorders were reported by 15.3% of the women in this study. Maternal hypertensive disorders in general, chronic hypertension, and gestational hypertension were not associated with hypospadias or its subtypes. Preeclampsia was associated with posterior hypospadias (aOR 3.09, 95% CI 1.49, 6.43), whether it was untreated (aOR 2.81, 95% CI 1.24, 6.38) or pharmacologically treated preeclampsia (aOR 4.96, 95% CI 1.08, 22.80). CONCLUSIONS: Our findings indicate that preeclampsia is associated with posterior hypospadias, irrespective of pharmacological treatment. This result supports the hypothesis of aetiological heterogeneity among the subtypes of hypospadias, with pregnancy-related risk factors being associated with the more severe types of hypospadias.

Surgical Complications in Children with CDH: A Multivariate Analysis.

INTRODUCTION: Several medical and surgical improvements in the treatment of congenital diaphragmatic hernia (CDH) patients have led to a higher survival rate. However, some of these improvements also lead to an increased morbidity rate. This study aims to determine the contribution different medical and surgical treatments have had on the development of surgical complications. METHOD: All CDH patients treated in a single centre between 2000 and 2015 were retrospectively evaluated. Multivariate logistic regression was used to estimate the independent effects of several treatment options that could influence the surgical outcome by adjustment for multiple risk factors. RESULTS: Sixty of the 197 surgically repaired CDH patients had surgical complications. There were more haemorrhagic complications in the ECMO compared to non-ECMO group (27% vs. 2%, p < 0.001). The use of inhaled nitric oxide was also significantly related to haemorrhage (OR = 13.0 (95% CI 1.1-159)). After adjustment for other risk factors, chylothorax was neither significantly associated with ECMO treatment (OR = 1.6 (95% CI 0.5-5.2) nor with patch repair (OR = 2.1: 95% CI 0.7-6.1). A recurrence occurred more often in patients with pulmonary hypertension (OR = 10.0 (95% CI 1.5-65.8) and after treatment with an abdominal patch (OR = 11.3: 95% CI 1.5-84.4). CONCLUSION: ECMO treatment and the inhalation of nitric oxide are used in the most severe CDH patients but are associated with a higher risk on surgical haemorrhage. The recurrence rate is associated with both the use of an abdominal patch and the presence of pulmonary hypertension, regardless of medical treatment.

Processing of Prediction Errors in Mentalizing Areas.

When seeing people perform actions, we are able to quickly predict the action's outcomes. These predictions are not solely based on the observed actions themselves but utilize our prior knowledge of others. It has been suggested that observed outcomes that are not in line with these predictions result in prediction errors, which require additional processing to be integrated or updated. However, there is no consensus on whether this is indeed the case for the kind of high-level social-cognitive processes involved in action observation. In this fMRI study, we investigated whether observation of unexpected outcomes causes additional activation in line with the processing of prediction errors and, if so, whether this activation overlaps with activation in brain areas typically associated with social-cognitive processes. In the first part of the experiment, participants watched animated movies of two people playing a bowling game, one experienced and one novice player. In cases where the player's score was higher or lower than expected based on their skill level, there was increased BOLD activity in areas that were also activated during a theory of mind task that participants performed in the second part of the experiment. These findings are discussed in the light of different theoretical accounts of human social-cognitive processing.

What do pediatric surgeons think about sexual issues in dealing with patients with anorectal malformations? The ARM-Net consortium members' opinion.

PURPOSE: Since pediatric surgeons aim to follow their patients with anorectal malformations (ARM) into adulthood the aim of this study was to investigate how pediatric surgeons deal with sexual issues related to ARM. METHODS: In 2018, a questionnaire was developed by the working group "Follow-up and sexuality" of the ARM-Net consortium and sent to all consortium-linked pediatric surgeons from 31 European pediatric surgical centers. Obtained data were statistically analyzed. RESULTS: Twenty-eight of 37 pediatric surgeons (18 males/10 females) answered the questionnaire. The majority of pediatric surgeons (82%) think they should talk about sexual issues with their patient. More than 50% of pediatric surgeons do not feel at all or only moderately confident discussing the topic of sexuality. Most pediatric surgeons require more support (96%) and wish to be trained in sexuality and sexual issues (78%) to feel confident towards their ARM-patients/parents. For optimal care, sexual issues with ARM-patients should be managed by a multidisciplinary team. CONCLUSIONS: Pediatric surgeons feel that sexuality is an important issue for their ARM-patients, which they are primarily responsible of but should be managed in concert with a multidisciplinary team. A training in sexuality is wished to feel more confident about this specific issue.

Clinical and genetic analyses of a Dutch cohort of 40 patients with a nephronophthisis-related ciliopathy.

BACKGROUND: Nephronophthisis is an autosomal recessive ciliopathy and important cause of end-stage renal disease (ESRD) in children and young adults. Diagnostic delay is frequent. This study investigates clinical characteristics, initial symptoms, and genetic defects in a cohort with nephronophthisis-related ciliopathy, to improve early detection and genetic counseling. METHODS: Forty patients from 36 families with nephronophthisis-related ciliopathy were recruited at university medical centers and online. Comprehensive clinical and genotypic data were recorded. Patients without molecular diagnosis were offered genetic analysis. RESULTS: Of 40 patients, 45% had isolated nephronophthisis, 48% syndromic diagnosis, and 7% nephronophthisis with extrarenal features not constituting a recognizable syndrome. Patients developed ESRD at median 13 years (range 5-47). Median age of symptom onset was 9 years in both isolated and syndromic forms (range 5-26 vs. 5-33). Common presenting symptoms were fatigue (42%), polydipsia/polyuria (33%), and hypertension (21%). Renal ultrasound showed small-to-normal-sized kidneys, increased echogenicity (65%), cysts (43%), and abnormal corticomedullary differentiation (32%). Renal biopsies in eight patients showed nonspecific signs of chronic kidney disease (CKD). Twenty-three patients (58%) had genetic diagnosis upon inclusion. Thirteen of those without a genetic diagnosis gave consent for genetic testing, and a cause was identified in five (38%). CONCLUSIONS: Nephronophthisis is genetically and phenotypically heterogeneous and should be considered in children and young adults presenting with persistent fatigue and polyuria, and in all patients with unexplained CKD. As symptom onset can occur into adulthood, presymptomatic monitoring of kidney function in syndromic ciliopathy patients should continue until at least age 30.

Parameterized Complexity of Theory of Mind Reasoning in Dynamic Epistemic Logic.

Theory of mind refers to the human capacity for reasoning about others' mental states based on observations of their actions and unfolding events. This type of reasoning is notorious in the cognitive science literature for its presumed computational intractability. A possible reason could be that it may involve higher-order thinking (e.g., 'you believe that I believe that you believe'). To investigate this we formalize theory of mind reasoning as updating of beliefs about beliefs using dynamic epistemic logic, as this formalism allows to parameterize 'order of thinking.' We prove that theory of mind reasoning, so formalized, indeed is intractable (specifically, PSPACE-complete). Using parameterized complexity we prove, however, that the 'order parameter' is not a source of intractability. We furthermore consider a set of alternative parameters and investigate which of them are sources of intractability. We discuss the implications of these results for the understanding of theory of mind.

Previous miscarriages and GLI2 are associated with anorectal malformations in offspring.

STUDY QUESTION: Are anorectal malformations (ARMs) associated with previous miscarriages or single nucleotide polymorphisms (SNPs) in the Bone Morphogenetic Protein 4 (BMP4) and GLI family zinc finger 2 (GLI2) genes? SUMMARY ANSWER: The SNP rs3738880 in GLI2 and miscarriages were associated with ARM, especially in patients with multiple congenital anomalies (MCA). WHAT IS KNOWN ALREADY: ARM are one of the most common birth defects of the gastrointestinal tract. The etiology is likely to be multifactorial, involving both environmental and genetic factors. SNPs in BMP4 and GLI2 genes were associated with ARM in non-Caucasian populations. During a patient information day, several mothers of ARM patients reported their concerns about previous miscarriages. STUDY DESIGN, SIZE, DURATION: A case-control study was performed among 427 ARM patients and 663 population-based controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: We examined the associations of ARM with SNPs in GLI2 and BMP4 using DNA samples of the children and associations with previous miscarriages using parental questionnaires. In addition, gene-gene and gene-environment interaction analyses were performed. MAIN RESULTS AND THE ROLE OF CHANCE: The SNP rs3738880 in GLI2 was associated with ARM, especially in patients with MCA (homozygous GG-genotype: odds ratio (OR): 2.1; 95% CI: 1.2, 3.7). We identified previous miscarriages as a new risk factor for ARM, especially when occurring in the pregnancy directly preceding the index pregnancy and in patients with MCA (OR: 2.1; 95% CI: 1.3, 3.5). No association with rs17563 in BMP4, nor gene-gene or gene-environment interactions were found. LIMITATIONS, REASONS FOR CAUTION: The possibility of recall errors for previous miscarriage, but we expect these errors to be limited, as a miscarriage is a major life event. In addition, potential misclassification regarding miscarriages and stillbirth, but sensitivity analyses showed that this did not influence our results. WIDER IMPLICATIONS OF THE FINDINGS: This study showed associations of ARM with rs3738880 in GLI2 and with previous miscarriages. Both associations were stronger in patients with MCA, showing the importance of stratifying the analyses by patients with isolated ARM or MCA. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Radboudumc. The authors have no conflict of interest to disclose.

To be precise, the details don't matter: On predictive processing, precision, and level of detail of predictions.

Many theoretical and empirical contributions to the Predictive Processing account emphasize the important role of precision modulation of prediction errors. Recently it has been proposed that the causal models used in human predictive processing are best formally modeled by categorical probability distributions. Crucially, such distributions assume a well-defined, discrete state space. In this paper we explore the consequences of this formalization. In particular we argue that the level of detail of generative models and predictions modulates prediction error. We show that both increasing the level of detail of the generative models and decreasing the level of detail of the predictions can be suitable mechanisms for lowering prediction errors. Both increase precision, yet come at the price of lowering the amount of information that can be gained by correct predictions. Our theoretical result establishes a key open empirical question to address: How does the brain optimize the trade-off between high precision and information gain when making its predictions?

Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT.

The leading cause of end-stage renal disease in children is attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Familial clustering and mouse models support the presence of monogenic causes. Genetic testing is insufficient as it mainly focuses on HNF1B and PAX2 mutations that are thought to explain CAKUT in 5­15% of patients. To identify novel, potentially pathogenic variants in additional genes, we designed a panel of genes identified from studies on familial forms of isolated or syndromic CAKUT and genes suggested by in vitro and in vivo CAKUT models. The coding exons of 208 genes were analyzed in 453 patients with CAKUT using next-generation sequencing. Rare truncating, splice-site variants, and non-synonymous variants, predicted to be deleterious and conserved, were prioritized as the most promising variants to have an effect on CAKUT. Previously reported disease-causing mutations were detected, but only five were fully penetrant causal mutations that improved diagnosis. We prioritized 148 candidate variants in 151 patients, found in 82 genes, for follow-up studies. Using a burden test, no significant excess of rare variants in any of the genes in our cohort compared with controls was found. Thus, in a study representing the largest set of genes analyzed in CAKUT patients to date, the contribution of previously implicated genes to CAKUT risk was significantly smaller than expected, and the disease may be more complex than previously assumed.