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In this study, exome sequencing yielded a genetic diagnosis in 16% of patients who had previously been evaluated to rule out known causes of intellectual disability. Severe intellectual disability, which is also referred to as cognitive impairment or mental retardation, affects approximately 0.5% of the population in Western countries 1 , 2 and represents an important health burden. A clinical diagnosis of severe intellectual disability is generally based on an IQ of less than 50 and substantial limitations in activities of daily living. In early childhood, the diagnosis is based on substantial developmental delays, including motor, cognitive, and speech delays. Children with different nonsyndromic forms of intellectual disability are clinically indistinguishable. Intellectual disability can be caused by nongenetic factors, such as infections and perinatal asphyxia. In developed countries, . . .

The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability. In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between patients and their parents to identify de-novo variants. 20 children and their parents from the KORA Augsburg Diabetes Family Study were investigated as controls. We enrolled 51 participants from the German Mental Retardation Network. 45 (88%) participants in the case group and 14 (70%) in the control group had de-novo variants. We identified 87 de-novo variants in the case group, with an exomic mutation rate of 1·71 per individual per generation. In the control group we identified 24 de-novo variants, which is 1·2 events per individual per generation. More participants in the case group had loss-of-function variants than in the control group (20/51 vs 2/20; p=0·022), suggesting their contribution to disease development. 16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A). We deemed at least six loss-of-function mutations in six novel genes to be disease causing. We also identified several missense alterations with potential pathogenicity. After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45–55% of patients with high locus heterogeneity. Autosomal recessive inheritance seems to contribute little in the outbred population investigated. The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes. Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions. German Ministry of Education and Research, European Commission 7th Framework Program, and Swiss National Science Foundation.

The Confidential Inquiry into premature deaths of people with intellectual disabilities in England was commissioned to provide evidence about contributory factors to avoidable and premature deaths in this population. The population-based Confidential Inquiry reviewed the deaths of people with intellectual disabilities aged 4 years and older who had been registered with a general practitioner in one of five Primary Care Trust areas of southwest England, who died between June 1, 2010, and May 31, 2012. A network of health, social-care, and voluntary-sector services; community contacts; and statutory agencies notified the Confidential Inquiry of all deaths of people with intellectual disabilities and provided core data. The Office for National Statistics provided data about the coding of individual cause of death certificates. Deaths were described as avoidable (preventable or amenable), according to Office for National Statistics definitions. Contributory factors to deaths were identified and quantified by the case investigator, verified by a local review panel meeting, and agreed by the Confidential Inquiry overview panel. Contributory factors were grouped into four domains: intrinsic to the individual, within the family and environment, care provision, and service provision. The deaths of a comparator group of people without intellectual disabilities but much the same in age, sex, and cause of death and registered at the same general practices as those with intellectual disabilities were also investigated. The Confidential Inquiry reviewed the deaths of 247 people with intellectual disabilities. Nearly a quarter (22%, 54) of people with intellectual disabilities were younger than 50 years when they died, and the median age at death was 64 years (IQR 52–75). The median age at death of male individuals with intellectual disabilities was 65 years (IQR 54–76), 13 years younger than the median age at death of male individuals in the general population of England and Wales (78 years). The median age at death of female individuals with intellectual disabilities was 63 years (IQR 54–75), 20 years younger than the median age at death for female individuals in the general population (83 years). Avoidable deaths from causes amenable to change by good quality health care were more common in people with intellectual disabilities (37%, 90 of 244) than in the general population of England and Wales (13%). Contributory factors to premature deaths in a subset of people with intellectual disabilities compared with a comparator group of people without intellectual disabilities included problems in advanced care planning (p=0·0003), adherence to the Mental Capacity Act (p=0·0008), living in inappropriate accommodation (p<0·0001), adjusting care as needs changed (p=0·009), and carers not feeling listened to (p=0·006). The Confidential Inquiry provides evidence of the substantial contribution of factors relating to the provision of care and health services to the health disparities between people with and without intellectual disabilities. It is imperative to examine care and service provision for this population as potentially contributory factors to their deaths—factors that can largely be ameliorated. Department of Health for England.

The authors discuss the substantive impact of recent advances in genomic technologies on the diagnosis and understanding of intellectual disability and autism. Intellectual disability, which is characterized by significant limitations in both intellectual functioning and adaptive behavior that begin before the age of 18 years, 1 affects 1.5 to 2% of the population in Western countries. 2 A diagnosis of intellectual disability is usually made when IQ testing reveals an IQ of less than 70, which means that often the diagnosis is not made until late childhood or early adulthood. However, most persons with intellectual disability are identified early in childhood on the basis of concern about developmental delays, which may include motor, cognitive, and speech delays. A genetic underpinning of this disorder has . . .

Joris Veltman, Han Brunner and colleagues report results of a family based exome sequencing study of ten individuals with unexplained mental retardation. They identified and validated de novo mutations in nine genes, six of which are likely to be pathogenic based on functional criteria, suggesting an important role for de novo point mutations in the etiology of unexplained mental retardation. The per-generation mutation rate in humans is high. De novo mutations may compensate for allele loss due to severely reduced fecundity in common neurodevelopmental and psychiatric diseases, explaining a major paradox in evolutionary genetic theory. Here we used a family based exome sequencing approach to test this de novo mutation hypothesis in ten individuals with unexplained mental retardation. We identified and validated unique non-synonymous de novo mutations in nine genes. Six of these, identified in six different individuals, are likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population.

Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) in schizophrenia and autism have reinforced the hypothesis that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense DNMs (0.101 vs 0.031, empirical P= 0.01, Benjamini–Hochberg-corrected P= 0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency ( P= 0.0029, corrected P= 0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation ( P= 2.01 × 10 − 5 , corrected P =2.1 × 10 − 3 ). Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2 , CHD8 and MECP2 ) and intellectual disability (for example, HUWE1 and TRAPPC9 ), supporting a shared genetic etiology between these disorders. Functionally CHD8 , MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome-based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis and treatment of mental disorders.

Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function. Genes in intellectual disability Although many gene defects have been identified for X-linked early-onset cognitive impairment, or intellectual disability, much less is known about genetic determinants of its autosomal recessive forms, which are more common. In a systematic attempt to shed more light on the molecular causes of the condition, homozygosity mapping, exon enrichment and next-generation sequencing were performed in 136 consanguineous families with the condition. Fifty novel candidate genes involved in intellectual disability were identified, as well as new mutations in several genes that had previously been implicated in neurological disorders. Many of the novel candidates interact with known intellectual-disability gene products and are predicted to act in processes that are vital for normal brain development and function.

To systematically summarise and analyse published research, which assessed balance control deficiencies of children and adolescents with intellectual disability (ID) in various balance domains by comparing their performance with that of typically developing (TD) peers. This study followed PRISMA principles and conducted a systematic search in six electronic databases in May 2025, including PubMed, Web of Science Core Collection, Scopus, EBSCO, LILACS, Cochrane Library, PEDro and Embase. The methodological quality of included studies was assessed using the Scottish Intercollegiate Guidelines Network checklist, and the certainty of the evidence was assessed via the GRADE approach. The meta-analysis was performed via RevMan 5.4. Descriptive analysis was performed if the data were insufficient. Fifteen studies were included and eight of which were pooled for meta-analysis. Children and adolescents with ID had poorer balance control than their TD peers. Specific to the various balance domains, individuals with ID presented substantially more difficulties in sensory orientation (eyes open: SMD = 0.89, 95% CI: 0.69 to 1.09, p  < 0.001; eyes closed: SMD = 0.44, 95% CI: 0.26 to 0.62, p <  0.001) and limits of stability (SMD = -0.91, 95% CI: -1.09 to -0.73, p <  0.001). They also encountered more hardships in gait stability (SMD = 0.52, 95% CI: 0.27 to 0.78, p <  0.001). For domain of anticipatory postural adjustments, inconsistent results were obtained. Children and adolescents with ID have deficient balance control ability than their TD peers. More researches are needed to comprehensively assess various domain of balance in this target group, especially those with longitudinal designs.

The purpose of this study was to investigate comorbid psychiatric disorders and psychotropic medication use among adults with autism spectrum disorder (ASD) ascertained as children during a 1980’s statewide Utah autism prevalence study ( n  = 129). Seventy-three individuals (56.6 %) met criteria for a current psychiatric disorder; 89 participants (69.0 %) met lifetime criteria for a psychiatric disorder. Caregivers reported a psychiatric diagnosis in 44 participants (34.1 %). Anxiety disorder had the highest current and lifetime prevalence (39.5 and 52.7 %, respectively). Participants with intellectual disability ( n  = 94, 72.8 %) were significantly less likely to have community-based diagnoses of anxiety (χ 2  = 5.37, p  = 0.02) or depression (χ 2  = 13.18, p  < 0.001) reported by caregivers. Seventy-six participants (58.9 %) were taking ≥1 psychotropic medication. Comorbid psychiatric disorders occur frequently in adults with ASD, though identifying these disorders poses a challenge in community settings. A greater understanding of the presentation of these conditions within this population will increase assessment validity and the potential for efficacious intervention.

Tarpey et al . carry out a large-scale systematic sequencing of the majority of X-chromosome coding exons from 208 families with multiple individuals with mental retardation and a pattern of transmission compatible with X linkage in order to identify XLMR-causative mutations. They find several mutations that appear to be causative in loci already known to be involved in XLMR, as well as new data about those loci, and make inferences about the role of the different classes of variants in these diseases. Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP , ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.