Reduced cone photoreceptor function and subtle systemic manifestations in two siblings with loss of SCLT1.

BACKGROUND: The sodium channel and clathrin linker 1 gene (SCLT1) has been involved in the pathogenesis of various ciliopathy disorders such as Bardet-Biedl syndrome, orofaciodigital syndrome type IX, and Senior-Løken syndrome. Detailed exams are warranted to outline all clinical features. Here, we present a family with a milder phenotype of SCLT1-related disease. MATERIAL AND METHODS: Comprehensive eye examination including fundus images, OCT, color vision, visual fields and electroretinography were performed. Affected individuals were assessed by a pediatrician and a medical geneticist for systemic features of ciliopathy. Investigations included echocardiography, abdominal ultrasonography, blood work-up for diabetes, liver and kidney function. Genetic testing included NGS retinal dystrophy panel, segregation analysis and transcriptome sequencing. RESULTS: Two male children, age 10 and 8 years, were affected with attention deficit hyperactivity disorder (ADHD), obesity and mild photophobia. The ophthalmic exam revealed reduced best-corrected visual acuity (BCVA), strabismus, hyperopia, astigmatism and moderate red-green defects. Milder changes suggesting photoreceptors disease were found on retinal imaging. Electroretinogram confirmed cone photoreceptors dysfunction. Genetic testing revealed a homozygous likely pathogenic, splice-site variant in SCLT1 gene NM_144643.3: c.1439 + 1del in the proband and in the affected brother. The unaffected parents were heterozygous for the SCLT1 variant. Transcriptome sequencing showed retention of intron 16 in the proband. CONCLUSIONS: In this report, we highlight the importance of further extensive diagnostics in patients with unexplained reduced vision, strabismus, refractive errors and ADHD spectrum disorders. SCLT1-related retinal degeneration is very rare and isolated reduced function of cone photoreceptors has not previously been observed.

Multimodal classification of molecular subtypes in pediatric acute lymphoblastic leukemia.

Genomic analyses have redefined the molecular subgrouping of pediatric acute lymphoblastic leukemia (ALL). Molecular subgroups guide risk-stratification and targeted therapies, but outcomes of recently identified subtypes are often unclear, owing to limited cases with comprehensive profiling and cross-protocol studies. We developed a machine learning tool (ALLIUM) for the molecular subclassification of ALL in retrospective cohorts as well as for up-front diagnostics. ALLIUM uses DNA methylation and gene expression data from 1131 Nordic ALL patients to predict 17 ALL subtypes with high accuracy. ALLIUM was used to revise and verify the molecular subtype of 281 B-cell precursor ALL (BCP-ALL) cases with previously undefined molecular phenotype, resulting in a single revised subtype for 81.5% of these cases. Our study shows the power of combining DNA methylation and gene expression data for resolving ALL subtypes and provides a comprehensive population-based retrospective cohort study of molecular subtype frequencies in the Nordic countries.

International Undiagnosed Diseases Programs (UDPs): components and outcomes.

Over the last 15 years, Undiagnosed Diseases Programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases, integrating research and clinical care to optimize diagnostic outcomes. This narrative review summarizes the published literature surrounding Undiagnosed Diseases Programs worldwide, including thirteen studies that evaluate outcomes and two commentary papers. Commonalities in the diagnostic and research process of Undiagnosed Diseases Programs are explored through an appraisal of available literature. This exploration allowed for an assessment of the strengths and limitations of each of the six common steps, namely enrollment, comprehensive clinical phenotyping, research diagnostics, data sharing and matchmaking, results, and follow-up. Current literature highlights the potential utility of Undiagnosed Diseases Programs in research diagnostics. Since participants have often had extensive previous genetic studies, research pipelines allow for diagnostic approaches beyond exome or whole genome sequencing, through reanalysis using research-grade bioinformatics tools and multi-omics technologies. The overall diagnostic yield is presented by study, since different selection criteria at enrollment and reporting processes make comparisons challenging and not particularly informative. Nonetheless, diagnostic yield in an undiagnosed cohort reflects the potential of an Undiagnosed Diseases Program. Further comparisons and exploration of the outcomes of Undiagnosed Diseases Programs worldwide will allow for the development and improvement of the diagnostic and research process and in turn improve the value and utility of an Undiagnosed Diseases Program.

Clinical, genetic and structural delineation of RPL13-related spondyloepimetaphyseal dysplasia suggest extra-ribosomal functions of eL13.

Spondyloepimetaphyseal dysplasia with severe short stature, RPL13-related (SEMD-RPL13), MIM#618728), is a rare autosomal dominant disorder characterized by short stature and skeletal changes such as mild spondylar and epimetaphyseal dysplasia affecting primarily the lower limbs. The genetic cause was first reported in 2019 by Le Caignec et al., and six disease-causing variants in the gene coding for a ribosomal protein, RPL13 (NM_000977.3) have been identified to date. This study presents clinical and radiographic data from 12 affected individuals aged 2-64 years from seven unrelated families, showing highly variable manifestations. The affected individuals showed a range from mild to severe short stature, retaining the same radiographic pattern of spondylar- and epi-metaphyseal dysplasia, but with varying severity of the hip and knee deformities. Two new missense variants, c.548 G>A, p.(Arg183His) and c.569 G>T, p.(Arg190Leu), and a previously known splice variant c.477+1G>A were identified, confirming mutational clustering in a highly specific RNA binding motif. Structural analysis and interpretation of the variants' impact on the protein suggests that disruption of extra-ribosomal functions of the protein through binding of mRNA may play a role in the skeletal phenotype of SEMD-RPL13. In addition, we present gonadal and somatic mosaicism for the condition.

No transfer of arousal from other's eyes in Williams syndrome.

Typically developing humans automatically synchronize their arousal levels, resulting in pupillary contagion, or spontaneous adaptation of pupil size to that of others. This phenomenon emerges in infancy and is believed to facilitate social interaction. Williams syndrome (WS) is a genetic condition characterized by a hyper-social personality and social interaction challenges. Pupillary contagion was examined in individuals with WS (n = 44), age-parallel-matched typically developing children and adults (n = 65), and infants (n = 79). Bayesian statistics were used. As a group, people with WS did not show pupillary contagion (Bayes factors supporting the null: 25-50) whereas control groups did. This suggests a very early emerging atypical developmental trajectory. In WS, higher pupillary contagion was associated with lower autistic symptoms of social communication. Diminished synchronization of arousal may explain why individuals with WS have social challenges, whereas synchronization of arousal is not a necessary correlate of high social motivation.

Reduced effects of social feedback on learning in Turner syndrome.

Turner syndrome is a genetic condition caused by a complete or partial loss of one of the X chromosomes. Previous studies indicate that Turner syndrome is associated with challenges in social skills, but the underlying mechanisms remain largely unexplored. A possible mechanism is a reduced social influence on learning. The current study examined the impact of social and non-social feedback on learning in women with Turner syndrome (n = 35) and a sex- and age-matched control group (n = 37). Participants were instructed to earn points by repeatedly choosing between two stimuli with unequal probabilities of resulting in a reward. Mastering the task therefore required participants to learn through feedback which of the two stimuli was more likely to be rewarded. Data were analyzed using computational modeling and analyses of choice behavior. Social feedback led to a more explorative choice behavior in the control group, resulting in reduced learning compared to non-social feedback. No effects of social feedback on learning were found in Turner syndrome. The current study thus indicates that women with Turner syndrome may be less sensitive to social influences on reinforcement learning, than the general population.

Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation.

Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on chromosome 15q11.2-q13. It is characterized by poor feeding and hypotonia in infancy, intellectual disability, behavioral abnormalities, dysmorphic features, short stature, obesity, and hypogonadism. PWS is not a known cancer predisposition syndrome, but previous investigations regarding the prevalence of cancer in these patients suggest an increased risk of developing specific cancer types such as myeloid leukemia and testicular cancer. We present the results from a Swedish national population-based cohort study of 360 individuals with PWS and 18,000 matched comparisons. The overall frequency of cancer was not increased in our PWS cohort, but we found a high frequency of pediatric cancers. We also performed whole-genome sequencing of blood- and tumor-derived DNAs from a unilateral dysgerminoma in a 13-year-old girl with PWS who also developed bilateral ovarian sex cord tumors with annular tubules. In germline analysis, there were no additional findings apart from the 15q11.2-q13 deletion of the paternal allele, while a pathogenic activating KIT mutation was identified in the tumor. Additionally, methylation-specific multiplex ligation-dependent probe amplification revealed reduced methylation at the PWS locus in the dysgerminoma but not in the blood. In conclusion, our register-based study suggests an increased risk of cancer at a young age, especially testicular and ovarian tumors. We found no evidence of a general increase in cancer risk in patients with PWS. However, given our limited observational time, further studies with longer follow-up times are needed to clarify the lifetime cancer risk in PWS. We have also described the second case of locus-specific loss-of-imprinting in a germ cell tumor in PWS, suggesting a possible mechanism of carcinogenesis.

Neurocutaneous Syndromes, Perinatal Factors, and the Risk of Childhood Cancer in Sweden.

Importance: Neurocutaneous syndromes are associated with cancer predisposition and sometimes associated with perinatal factors. A better understanding of the association between neurocutaneous syndromes, perinatal factors, and childhood cancer is key for earlier cancer detection. Objective: To evaluate the association of neurocutaneous syndromes and perinatal factors with childhood cancer risk in a cohort of Swedish children. Design, Setting, and Participants: In this nationwide cohort study, all children and adolescents up to age 20 years, from 1973 to 2015, were identified through the Swedish National Medical Birth Register (MBR), provided they had information on both biological parents. Analyses were conducted from April 2021 through May 2023. Exposures: Diagnoses of neurocutaneous syndromes were obtained from the MBR, National Patient Register, and Cause of Death register. Perinatal factors (birth weight, gestational age, birth weight by gestational age, 5-minute Apgar score, and head circumference) were obtained from the MBR. Main Outcomes and Measures: Childhood cancer risk (<20 years at diagnosis; identified from the National Cancer Register), including leukemia, lymphoma, and central nervous system (CNS) tumors. Results: Among 4 173 108 included children (2 143 133 [51.4%] male, median [IQR] follow-up 20 [9.7-20] years), 1783 had neurofibromatosis type 1 (NF1), 444 tuberous sclerosis, 63 von Hippel-Lindau disease, and 39 ataxia-telangiectasia. An increased cancer risk was observed among children with any neurocutaneous syndrome (HR, 34.9; 95% CI, 30.8-39.6) and was particularly pronounced for CNS tumors (HR, 111.7; 95% CI, 96.8-128.8), except among children with ataxia-telangiectasia, where the increased risk was associated with lymphomas (HR, 233.1; 95% CI, 75.0-724.1). Leukemia risk was increased only among children with NF1 (HR, 4.1; 95% CI, 1.7-9.8). Several perinatal factors, including high birth weight, being born large for gestational age, preterm birth, low 5-minute Apgar score, and large head circumference had lesser associations with childhood cancer. Adjusting for neurocutaneous syndromes did not affect these associations. Conclusions and Relevance: In this nationwide cohort study, neurocutaneous syndromes were associated with an increased risk of childhood cancer, especially CNS tumors. Several perinatal factors had lesser associations with childhood cancer, independently of the presence of neurocutaneous syndromes. Other biological mechanisms likely underlie the association between perinatal factors and childhood cancer.

Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions.

RNA binding motif protein X-linked (RBMX) encodes the heterogeneous nuclear ribonucleoprotein G (hnRNP G) that regulates splicing, sister chromatid cohesion and genome stability. RBMX knock down experiments in various model organisms highlight the gene's importance for brain development. Deletion of the RGG/RG motif in hnRNP G has previously been associated with Shashi syndrome, however involvement of other hnRNP G domains in intellectual disability remain unknown. In the current study, we present the underlying genetic and molecular cause of Gustavson syndrome. Gustavson syndrome was first reported in 1993 in a large Swedish five-generation family presented with profound X-linked intellectual disability and an early death. Extensive genomic analyses of the family revealed hemizygosity for a novel in-frame deletion in RBMX in affected individuals (NM_002139.4; c.484_486del, p.(Pro162del)). Carrier females were asymptomatic and presented with skewed X-chromosome inactivation, indicating silencing of the pathogenic allele. Affected individuals presented minor phenotypic overlap with Shashi syndrome, indicating a different disease-causing mechanism. Investigation of the variant effect in a neuronal cell line (SH-SY5Y) revealed differentially expressed genes enriched for transcription factors involved in RNA polymerase II transcription. Prediction tools and a fluorescence polarization assay imply a novel SH3-binding motif of hnRNP G, and potentially a reduced affinity to SH3 domains caused by the deletion. In conclusion, we present a novel in-frame deletion in RBMX segregating with Gustavson syndrome, leading to disturbed RNA polymerase II transcription, and potentially reduced SH3 binding. The results indicate that disruption of different protein domains affects the severity of RBMX-associated intellectual disabilities.

Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer.

PURPOSE: Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored. METHODS: We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes. RESULTS: During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%). CONCLUSION: Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.

Cognitive profile in adult women with turner syndrome: IQ split and associations with ADHD and ASD.

INTRODUCTION: The behavioural phenotype in Turner syndrome (TS) is associated with an uneven cognitive profile and social and executive difficulties. Still, studies in adult populations of TS are scarce, and the interactions between different behavioural domains are unclear. The aim of this study was to examine the cognitive profile in relation to measures of ADHD and ASD in a Swedish sample of 30 adult women with TS. METHODS: Standardized psychological tests and questionnaires were used for behavioural assessments in a sample of adult women with a diagnosis of TS (n = 30). Both frequentist and Bayesian statistics were applied. RESULTS: The cognitive profile was characterized by a verbal > non-verbal intelligence quotient (IQ) split, and 77% of the sample displayed a split exceeding cut-off for clinical significance. Symptoms on screening measures reaching thresholds for ADHD were reported in two of the 30 participants (7%) and thresholds for autism spectrum disorders (ASD) in one participant (3%). Bayesian statistics gave substantial evidence for no association between the IQ split and symptoms of ADHD/ASD. CONCLUSIONS: These results show that the TS phenotype in adulthood is associated with a clinically significant uneven cognitive profile, and particular impairments in integrative executive functions.

Precision medicine in rare diseases: What is next?

Molecular diagnostics is a cornerstone of modern precision medicine, broadly understood as tailoring an individual's treatment, follow-up, and care based on molecular data. In rare diseases (RDs), molecular diagnoses reveal valuable information about the cause of symptoms, disease progression, familial risk, and in certain cases, unlock access to targeted therapies. Due to decreasing DNA sequencing costs, genome sequencing (GS) is emerging as the primary method for precision diagnostics in RDs. Several ongoing European initiatives for precision medicine have chosen GS as their method of choice. Recent research supports the role for GS as first-line genetic investigation in individuals with suspected RD, due to its improved diagnostic yield compared to other methods. Moreover, GS can detect a broad range of genetic aberrations including those in noncoding regions, producing comprehensive data that can be periodically reanalyzed for years to come when further evidence emerges. Indeed, targeted drug development and repurposing of medicines can be accelerated as more individuals with RDs receive a molecular diagnosis. Multidisciplinary teams in which clinical specialists collaborate with geneticists, genomics education of professionals and the public, and dialogue with patient advocacy groups are essential elements for the integration of precision medicine into clinical practice worldwide. It is also paramount that large research projects share genetic data and leverage novel technologies to fully diagnose individuals with RDs. In conclusion, GS increases diagnostic yields and is a crucial step toward precision medicine for RDs. Its clinical implementation will enable better patient management, unlock targeted therapies, and guide the development of innovative treatments.

The cost-effectiveness of whole genome sequencing in neurodevelopmental disorders.

Whole genome sequencing (WGS) has the potential to be a comprehensive genetic test, especially relevant for individuals with neurodevelopmental disorders, syndromes and congenital malformations. However, the cost consequences of using whole genome sequencing as a first-line genetic test for these individuals are not well understood. The study objective was to compare the healthcare costs and diagnostic yield when WGS is performed as the first-line test instead of chromosomal microarray analysis (CMA). Two cohorts were analyzed retrospectively using register data, cohort CMA (418 patients referred for CMA at the department of Clinical Genetics, Karolinska University Hospital, during 2015) and cohort WGS (89 patients included in a WGS-first prospective study in 2017). The analysis compared healthcare consumption over a 2-year period after referral for genetic testing, the diagnostic yield over a 2- and 3-year period after referral was also compiled. The mean healthcare cost per patient in cohort WGS was $2,339 lower compared to cohort CMA ($ - 2339, 95% CI - 12,238-7561; P = 0.64) including higher costs for genetic investigations ($1065, 95% CI 834-1295; P < 0.001) and lower costs for outpatient care ($ - 2330, 95% CI - 3992 to (- 669); P = 0.006). The diagnostic yield was 23% higher for cohort WGS (cohort CMA 20.1%, cohort WGS 24.7%) (0.046, 95% CI - 0.053-0.145; P = 0.36). WGS as a first-line diagnostic test for individuals with neurodevelopmental disorders is associated with statistically non-significant lower costs and higher diagnostic yield compared with CMA. This indicates that prioritizing WGS over CMA in health care decision making will yield positive expected outcomes as well as showing a need for further research.

Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.

PURPOSE: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. METHODS: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. RESULTS: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. CONCLUSION: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Precision medicine and rare diseases in pediatric urology.

Precision Medicine holds promise for helping us manage specific phenotypes of common diseases. For rare diseases such as hypospadias, DSD, and pediatric solid tumors, it can also reveal underlying risk factors and pathogenesis. Professors Ann Nordgren and Anna Lindstrand share their experiences in the development and ongoing initiatives of the Swedish national project on Precision Medicine and how it could change the care of pediatric urology patients.

Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders.

Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Social feedback enhances learning in Williams syndrome.

Williams syndrome (WS) is a rare genetic condition characterized by high social interest and approach motivation as well as intellectual disability and anxiety. Despite the fact that social stimuli are believed to have an increased intrinsic reward value in WS, it is not known whether this translates to learning and decision making. Genes homozygously deleted in WS are linked to sociability in the general population, making it a potential model condition for understanding the social brain. Probabilistic reinforcement learning was studied with either social or non-social rewards for correct choices. Social feedback improved learning in individuals with Williams syndrome but not in typically developing controls or individuals with other intellectual disabilities. Computational modeling indicated that these effects on social feedback were mediated by a shift towards higher weight given to rewards relative to punishments and increased choice consistency. We conclude that reward learning in WS is characterized by high volatility and a tendency to learn how to avoid punishment rather than how to gain rewards. Social feedback can partly normalize this pattern and promote adaptive reward learning.

Williams syndrome: reduced orienting to other's eyes in a hypersocial phenotype.

Williams syndrome (WS) is a rare genetic condition associated with high sociability, intellectual disability, and social cognitive challenges. Attention to others' eyes is crucial for social understanding. Orienting to, and from other's eyes was studied in WS (n = 37, mean age = 23, age range 9-53). The WS group was compared to a typically developing comparison participants (n = 167) in stratified age groups from infancy to adulthood. Typically developing children and adults were quicker and more likely to orient to eyes than the mouth. This bias was absent in WS. The WS group had reduced peak saccadic velocities, indicating hypo-arousal. The current study indicates reduced orienting to others' eyes in WS, which may affect social interaction skills.

Pupillary response in reward processing in adults with major depressive disorder in remission.

OBJECTIVE: Major depressive disorder (MDD) is associated with impaired reward processing and reward learning. The literature is inconclusive regarding whether these impairments persist after remission. The current study examined reward processing during a probabilistic learning task in individuals in remission from MDD (n = 19) and never depressed healthy controls (n = 31) matched for age and sex. The outcome measures were pupil dilation (an indirect index of noradrenergic activity and arousal) and computational modeling parameters. METHOD: Participants completed two versions (facial/nonfacial feedback) of probabilistic reward learning task with changing contingencies. Pupil dilation was measured with a corneal reflection eye tracker. The hypotheses and analysis plan were preregistered. RESULT: Healthy controls had larger pupil dilation following losses than gains (p <.001), whereas no significant difference between outcomes was found in individuals with a history of MDD, resulting in an interaction between group and outcome (ß = 0.81, SE = 0.34, t = 2.37, p = .018). The rMDD group also achieved lower mean score at the last trial (t[46.77] = 2.12, p = .040) as well as a smaller proportion of correct choices (t[46.70] = 2.09, p = .041) compared with healthy controls. CONCLUSION: Impaired reward processing may persist after remission from MDD and could constitute a latent risk factor for relapse. Measuring pupil dilation in a reward learning task is a promising method for identifying reward processing abnormalities linked to MDD. The task is simple and noninvasive, which makes it feasible for clinical research.

ZEB2 haploinsufficient Mowat-Wilson syndrome induced pluripotent stem cells show disrupted GABAergic transcriptional regulation and function.

Mowat-Wilson syndrome (MWS) is a severe neurodevelopmental disorder caused by heterozygous variants in the gene encoding transcription factor ZEB2. Affected individuals present with structural brain abnormalities, speech delay and epilepsy. In mice, conditional loss of Zeb2 causes hippocampal degeneration, altered migration and differentiation of GABAergic interneurons, a heterogeneous population of mainly inhibitory neurons of importance for maintaining normal excitability. To get insights into GABAergic development and function in MWS we investigated ZEB2 haploinsufficient induced pluripotent stem cells (iPSC) of MWS subjects together with iPSC of healthy donors. Analysis of RNA-sequencing data at two time points of GABAergic development revealed an attenuated interneuronal identity in MWS subject derived iPSC with enrichment of differentially expressed genes required for transcriptional regulation, cell fate transition and forebrain patterning. The ZEB2 haploinsufficient neural stem cells (NSCs) showed downregulation of genes required for ventral telencephalon specification, such as FOXG1, accompanied by an impaired migratory capacity. Further differentiation into GABAergic interneuronal cells uncovered upregulation of transcription factors promoting pallial and excitatory neurons whereas cortical markers were downregulated. The differentially expressed genes formed a neural protein-protein network with extensive connections to well-established epilepsy genes. Analysis of electrophysiological properties in ZEB2 haploinsufficient GABAergic cells revealed overt perturbations manifested as impaired firing of repeated action potentials. Our iPSC model of ZEB2 haploinsufficient GABAergic development thus uncovers a dysregulated gene network leading to immature interneurons with mixed identity and altered electrophysiological properties, suggesting mechanisms contributing to the neuropathogenesis and seizures in MWS.