Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.

Thrombocytopenia has a variety of different etiologies, both acquired and hereditary. Inherited thrombocytopenia may be associated with other symptoms (syndromic forms) or may be strictly isolated. To date, only about half of all the familial forms of thrombocytopenia have been accounted for in terms of well-defined genetic abnormalities. However, data are limited on the nature and frequency of the underlying causative genetic variants in individuals with mild isolated nonsyndromic thrombocytopenia. Thirteen known or candidate genes for isolated thrombocytopenia were included in a gene panel analysis in which targeted next-generation sequencing was performed on 448 French blood donors with mild isolated nonsyndromic thrombocytopenia. A total of 68 rare variants, including missense, splice site, frameshift, nonsense, and in-frame variants (all heterozygous) were identified in 11 of the 13 genes screened. Twenty-nine percent (N = 20) of the variants detected were absent from both the French Exome Project and gnomAD exome databases. Using stringent criteria and an unbiased approach, we classified seven predicted loss-of-function variants (three in ITGA2B and four in TUBB1) and four missense variants (one in GP1BA, two in ITGB3 and one in ACTN1) as being pathogenic or likely pathogenic. Altogether, they were found in 13 members (approx. 3%) of our studied cohort. We present the results of gene panel sequencing of known and candidate thrombocytopenia genes in mild isolated nonsyndromic thrombocytopenia. Pathogenic and likely pathogenic variants in five known thrombocytopenia genes were identified, accounting for approximately 3% of individuals with the condition.

Analysis of population structures and genome local ancestry hasbecome increasingly important in population and disease genetics. With the advance of next generation sequencing technologies, complete genetic variants in individuals' genomes are quickly generated, providing unprecedented opportunities for learning population evolution histories and identifying local genetic signatures at the SNP resolution. The successes of those studies critically rely on accurate and powerful computational tools that can fully utilize the sequencing information. Although many algorithms have been developed for population structure inference and admixture mapping, many of them only work for independent SNPs in genotype or haplotype format, and require a large panel of reference individuals. In this paper, we propose a novel probabilistic method for detecting population structure and local admixture. The method takes input of sequencing data, genotype data and haplotype data. The method characterizes the dependence of genetic variants via haplotype segmentation, such that all variants detected in a sequencing study can be fully utilized for inference. The method further utilizes a infinite-state Bayesian Markov model to perform de novo stratification and admixture inference. Using simulated datasets from HapMapII and 1000Genomes, we show that our method performs superior than several existing algorithms, particularly when limited or no reference individuals are available. Our method is applicable to not only human studies but also studies of other species of interests, for which little reference information is available.Software Availability: http://stat.psu.edu/~yuzhang/software/dbm.tar

Anthracyclines are chemotherapeutic agents widely used to treat a variety of cancers, and these drugs have revolutionized our management of cancer patients. The dose-dependent cardiotoxicity of anthracyclines, however, remains one of the leading causes of chemotherapy treatment-associated mortality in cancer survivors. Patient threshold doses leading to anthracycline-induced cardiotoxicity (AIC) are highly variable among affected patients. This variability is largely ascribed to genetic variants in individuals' genomes. Here, we briefly discuss the prevailing mechanisms underlying the pathogenesis of AIC, and then, we review the genetic variants, mostly identified through human genetic approaches and identified in cancer survivors. The identification of all genetic susceptibilities and elucidation of underlying mechanisms of AIC can help improve upfront risk prediction assessment for potentially severe cardiotoxicity disease and provide valuable insights into the understanding of AIC pathophysiology, which can be further leveraged to develop targeted pharmacogenetic therapies for those at high risk.

BackgroundTraditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD variants to head and neck paraganglioma (HNPGL). However, in a recent...

Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. To identify genetic variants contributing to disease risk in familial PD. A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design. The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing. TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

Mutation Detection Large-scale sequencing studies have set out to determine the low-frequency pathogenic genetic variants in individu als and populations. However, Chen et al. demonstrate that many so-called low-frequency genetic variants in large public databases may be due to DNA damage. They scored libraries sequenced with and without a DNA damage-repairing enzymatic mix to assess the proportion of true rare variants. It remains to be seen how best to repair DNA before sequencing to provide more accurate assessments of mutation. Science , this issue p. [752][1] [1]: /lookup/doi/10.1126/science.aai8690

Osteogenesis imperfecta (OI) is a rare genetic disorder also known as a “brittle bone disease.” Around 90% of patients with OI harbor loss‐of‐function or dominant negative pathogenic variants in the COL1A1 and COL1A2 genes, which code for collagen type I α1 and α2 chains. Collagen‐related forms of the disorder are classified as Sillence OI types I–IV. OI phenotype expression ranges from mild to lethal. The current study aims to evaluate associations between interfamilial and intrafamilial phenotypic variability and genotype characteristics of patients with collagen‐related OI. The study was based on a systematic review of collagen‐related OI cases from the University of Tartu OI database (n = 137 individuals from 81 families) and the Dalgleish database (n = 479 individuals). Interfamilial variability analysis has shown that 17.74% of all studied OI‐related variants were associated with the same phenotype. The remaining 82.26% of pathogenic variants were associated with variable phenotypes. Additionally, higher interfamilial variability correlated with the COL1A1 gene (P value = 0.001) and dominant‐negative variants (P value = 0.0007). Within intrafamilial variability, 32.81% families had increasing or decreasing OI phenotype severity across generations. Higher intrafamilial variability of phenotypes correlated with the collagen I dominant negative variants (P value = 0.0246). The current study shows that, in line with other phenotype modification factors, OI interfamilial and intrafamilial diversity potential is associated with the genotype characteristics of the OI‐causing pathogenic variants. The results of the current study may advance knowledge of OI phenotype modification as well as assist family planning and the evaluation of disease progression in subsequent generations.

Effective social interactions depend on the seamless integration of three essential elements: thinking, feeling, and doing. Thinking encompasses social cognitive processes like understanding social norms, interpreting contextual cues, and reading nonverbal signals. Feeling involves emotional regulation, which can positively or negatively influence our thoughts and behaviors. Doing pertains to the execution of social skills, where we make and carry out decisions smoothly during interactions. These elements operate simultaneously and dynamically, adding complexity to social interactions. This article underscores the significance of these components and presents a conceptual framework for understanding social interaction skills in youth with autism. Seminal and contemporary research studies will be reviewed and integrated with the author’s experience as both a researcher and clinician in the field of autism over the last four decades. The conceptual model presented in this article highlights the necessity for strategies that enhance social cognition, improve emotional regulation, and facilitate behavioral execution. Individuals with autism often experience significant difficulties in social communication and interpersonal functioning [1]. These challenges affect both social cognitive processing, such as perspective-taking, joint attention, cognitive flexibility, restricted interests, and social problem-solving, and social skills, including initiating interactions, responding to others, and maintaining reciprocal interactions. Social skill difficulties often result in substantial impairments in forming and maintaining peer relationships and are linked to negative outcomes like social failure, peer rejection, bullying, anxiety, depression, academic issues, substance abuse, suicidal ideation, delinquency, and other forms of psychopathology [2-6]. Longitudinal research shows that social skills at the start of kindergarten are strong indicators of future employment, criminal behavior, mental health, substance abuse, and educational attainment in young adulthood [7]. Despite its critical importance, finding effective social skills programs for children and youth with autism has been a challenging task for both practitioners and researchers [8]. There is a pressing need for effective social skills programs for children and youth with autism, however teaching these skills effectively is a complex and difficult process [8]. Numerous literature reviews and meta-analytical studies have examined social skills interventions for children and adolescents with and without autism [9-15]. While these studies show varied and conflicting results regarding the main effects of interventions, they consistently highlight issues with poor generalization of skills. Social skill difficulties are a pervasive and enduring feature of autism, and generalizing learned social skills can be particularly challenging for this group. Effective social skills programs that enhance acquisition of social skills and promote skill generalization are crucial for children with autism. Successful social interactions incorporate the successful integration of three integrated components: Thinking (i.e., social cognitive processing), Feeling (i.e., emotional regulation), and Doing (i.e., behavioral execution) [2]. For example, every social interaction requires us to engage in social cognitive processing. This involves understanding social rules, social norms and customs, reading contextual cues from the environment, and interpreting the nonverbal signals of those with whom we are interacting. This cognitive processing also helps us to consider and understand another person’s perspective while also monitoring and regulating our own thoughts, feelings, and behaviors. Ultimately, these processes lead us to make more effective behavioral decisions. Alongside cognitive processing, we also experience emotions that can influence our thoughts and behaviors in both positive and negative ways. Positive emotions enhance social engagement and pleasure, while negative emotions can cause physiological stress, self-defeating thoughts, and behavioral avoidance. Therefore, successful social interactions require not only effective social-cognitive processing but also the ability to actively regulate emotions that might hinder performance. In addition to effective social-cognitive processing and emotional regulation, successful social interactions also require the integration of one additional component: behavioral execution, or Doing. Social interactions are dynamic performances that demand us to continually make behavioral decisions and then execute them smoothly and effectively. This involves coordinating our motor movements and language production while staying in sync and rhythm with the movements and speech of the person with whom we are interacting. Lastly, and perhaps most critically, it’s important to remember that all these components-Thinking, Feeling, and Doing-happen simultaneously during social interactions. Makes solving algebraic equations seem easy by comparison, doesn’t it? This article explores these three interconnected components, particularly in the context of social interactions of youth with autism and lays the conceptual groundwork for the development and implementation of effective social skill programming.

Association of dyslipidemia with single nucleotide polymorphisms of the cholesteryl ester transfer protein gene and cardiovascular disease risk factors in a highly admixed population

High throughput sequencing is discovering many likely causative genetic variants in individuals with cerebral palsy. Some investigators have suggested that this changes the clinical diagnosis of cerebral palsy and that these individuals should be removed from this diagnostic category. Cerebral palsy is a neurodevelopmental disorder diagnosed on clinical signs, not etiology. All nonprogressive permanent disorders of movement and posture attributed to disturbances that occurred in the developing fetal and infant brain can be described as “cerebral palsy.” This definition of cerebral palsy should not be changed, whatever the cause. Reasons include stability, utility and accuracy of cerebral palsy registers, direct access to services, financial and social support specifically offered to families with cerebral palsy, and community understanding of the clinical diagnosis. Other neurodevelopmental disorders, for example, epilepsy, have not changed the diagnosis when genomic causes are found. The clinical diagnosis of cerebral palsy should remain, should prompt appropriate genetic studies and can subsequently be subclassified by etiology.

Population stratification is one of the major sources of confounding in genetic association studies, potentially causing false-positive and false-negative results. Here, we present a novel approach for the identification of population substructure in high-density genotyping data/next generation sequencing data. The approach exploits the co-appearances of rare genetic variants in individuals. The method can be applied to all available genetic loci and is computationally fast. Using sequencing data from the 1000 Genomes Project, the features of the approach are illustrated and compared to existing methodology (i.e. EIGENSTRAT). We examine the effects of different cutoffs for the minor allele frequency on the performance of the approach. We find that our approach works particularly well for genetic loci with very small minor allele frequencies. The results suggest that the inclusion of rare-variant data/sequencing data in our approach provides a much higher resolution picture of population substructure than it can be obtained with existing methodology. Furthermore, in simulation studies, we find scenarios where our method was able to control the type 1 error more precisely and showed higher power. dmitry.prokopenko@uni-bonn.de Supplementary data are available at Bioinformatics online.

Effect of sampling on the extent and accuracy of the inferred genetic history of recombining genome

Identification of rod- and cone-specific expression signatures to identify candidate genes for retinal disease

Leber congenital amaurosis (LCA) encompasses a group of severe inherited retinal dystrophies (IRDs) responsible for early childhood blindness. There are currently 25 genes implicated in the pathogenesis of these diseases, and identification of disease-causing variants will be required for personalised therapies. Whole exome and whole genome sequencing is informative for detecting novel disease-causing genes, whilst next-generation sequencing has excelled at detecting novel variants in known disease-causing genes.A global effort will be required to identify patient populations for early intervention. At the Australian Inherited Retinal Disease Registry and DNA Bank, we seek to identify genetic variants in individuals with IRDs in the Australian population to identify potential candidates for clinical trials, to inform clinical management of patients including reproductive options and to expand existing knowledge of IRDs.Due to the diversity of genes implicated, personalised strategies are likely to be the benchmark for treating these diseases, and a combined approach of different therapies may be optimal in treating some of these diseases.

The emerging genetic basis of spontaneous coronary artery dissection (SCAD) has been defined as both partially complex and monogenic in some patients, involving variants predominantly in genes known to underlie vascular connective tissue diseases (CTDs). The effect of these genetic influences has not been defined in high-risk SCAD phenotypes, and the identification of a high-risk subgroup of individuals may help to guide clinical genetic evaluations of SCAD. To identify and quantify the burden of rare genetic variation in individuals with SCAD with high-risk clinical features. Whole-exome sequencing (WES) was performed for subsequent case-control association analyses and individual variant annotation among individuals with high-risk SCAD. Genetic variants were annotated for pathogenicity by in-silico analysis of genes previously defined by sequencing for vascular CTDs and/or SCAD, as well as genes prioritized by genome-wide association study (GWAS) and colocalization of arterial expression quantitative trait loci. Unbiased genome-wide association analysis of the WES data was performed by comparing aggregated variants in individuals with SCAD to healthy matched controls or the Genome Aggregation Database (gnomAD). This study was conducted at a tertiary care center. Individuals in the Canadian SCAD Registry genetics study with a high-risk SCAD phenotype were selected and defined as peripartum SCAD, recurrent SCAD, or SCAD in an individual with family history of arteriopathy. Burden of genetic variants defined by DNA sequencing in individuals with high-risk SCAD. This study included a total of 336 participants (mean [SD] age, 53.0 [9.5] years; 301 female participants [90%]). Variants in vascular CTD genes were identified in 17.0% of individuals (16 of 94) with high-risk SCAD and were enriched (OR, 2.6; 95% CI, 1.6-4.2; P = 7.8 × 10-4) as compared with gnomAD, with leading significant signals in COL3A1 (OR, 13.4; 95% CI, 4.9-36.2; P = 2.8 × 10-4) and Loeys-Dietz syndrome genes (OR, 7.9; 95% CI, 2.9-21.2; P = 2.0 × 10-3). Variants in GWAS-prioritized genes, observed in 6.4% of individuals (6 of 94) with high-risk SCAD, were also enriched (OR, 3.6; 95% CI, 1.6-8.2; P = 7.4 × 10-3). Variants annotated as likely pathogenic or pathogenic occurred in 4 individuals, in the COL3A1, TGFBR2, and ADAMTSL4 genes. Genome-wide aggregated variant testing identified novel associations with peripartum SCAD. In this genetic study, approximately 1 in 5 individuals with a high-risk SCAD phenotype harbored a rare genetic variant in genes currently implicated for SCAD. Genetic screening in this subgroup of individuals presenting with SCAD may be considered.