Cases Of Intellectual Disability Research Articles

Integrating genomic variants and developmental milestones to predict cognitive and adaptive outcomes in autistic children.

Although the first signs of autism are often observed as early as 18-36 months of age, there is a broad uncertainty regarding future development, and clinicians lack predictive tools to identify those who will later be diagnosed with co-occurring intellectual disability (ID). Here, we developed predictive models of ID in autistic children (n=5,633 from three cohorts), integrating different classes of genetic variants alongside developmental milestones. The integrated model yielded an AUC ROC=0.65, with this predictive performance cross-validated and generalised across cohorts. Positive predictive values reached up to 55%, accurately identifying 10% of ID cases. The ability to stratify the probabilities of ID using genetic variants was up to twofold greater in individuals with delayed milestones compared to those with typical development. These findings underscore the potential of models in neurodevelopmental medicine that integrate genomics and clinical observations to predict outcomes and target interventions.

Genetic diagnostic approach to intellectual disability and multiple congenital anomalies in Indonesia.

Intellectual disability (ID) and multiple congenital anomalies (MCA) are major contributors to infant mortality, childhood morbidity, and long-term disability, with multifactorial aetiology including genetics. We aim to set a diagnostic approach for genetic evaluation of patients with ID and MCA, which can be applied efficiently with a good diagnostic rate in Indonesia or other low resources settings. Out of 131 ID cases, twenty-three individuals with ID/global developmental delay (GDD) and MCA were selected from two-steps of dysmorphology screening and evaluation. Genetic analysis included chromosomal microarray (CMA) analysis, targeted panel gene sequencing, and exome sequencing (ES). CMA revealed conclusive results for seven individuals. Meanwhile, two out of four cases were diagnosed by targeted gene sequencing. Five out of seven individuals were diagnosed using ES testing. Based on the experience, a novel and comprehensive flowchart combining thorough physical and dysmorphology evaluation, followed by suitable genetic tests is proposed as a diagnostic approach to elucidate the genetic factor(s) of ID/GDD and MCA in low resources settings such as Indonesia.

Cerebellar Atrophy and Epilepsy in Twins with a Novel SCN8A Mutation

Abstract Purpose Pathogenic SCN8A variants are associated with a wide spectrum of clinical presentation, ranging from mild to severe epileptic phenotypes, cases of intellectual disability, or movement disorders without epilepsy. Ataxia and cerebellar atrophy are rarely described as components of the disease phenotype. Case Presentation We present the cases of male twins, born after normal pregnancy and delivery, both with normal neuropsychological but with delayed motor development in the first 2 years of life. Between 8 months and 9 years of age, the boys experienced generalized tonic-clonic seizures, several times per year. When 9 years old, the children suffered an increase in seizure frequency, and the family reported gradual worsening in coordination, speech, communication, and social skills. When 9 and a half years of age, the patients were admitted to the Clinic of Child Neurology for the first time. They both had coordination syndrome (intention tremor, dysmetria, dysdiadochokinesia) that had worsened compared with previous reports, and magnetic resonance imaging of the brain showed cerebellar atrophy. The genetic testing confirmed a mutation c.2617G > T, p.Gly873Cys in SCN8A gene. After adding lamotrigine to valproate and levetiracetam, and adjusting the dosage of valproate and levetiracetam, we observed good seizure control accompanied by improvement in the coordination syndrome. Conclusion The cerebellar atrophy in our patients is likely due to the underlying sodium channelopathy, as it was presented at the time of the seizure worsening, but we cannot exclude the role of the epileptic seizures as the worsening of the coordination syndrome accompanied the seizure aggravation, and the tendency toward improvement was evident after seizure control.

Intellectual disability in the children of the Avon Longitudinal Study of Parents and Children (ALSPAC).

Background: Intellectual disability (ID) describes a neurodevelopmental condition involving impaired cognitive and functional ability. Here, we describe a multisource variable of ID using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Methods: The multisource indicator variable for ID was derived from i) IQ scores less than 70 measured at age 8 and at age 15, ii) free text fields from parent reported questionnaires, iii) school reported provision of educational services for individuals with a statement of special educational needs for cognitive impairments, iv) from relevant READ codes contained in GP records, iv) international classification of disease diagnoses contained in electronic hospital records and hospital episode statistics and v) recorded interactions with mental health services for ID contained within the mental health services data set. A case of ID was identified if two or more sources indicated ID. A second indicator, labelled as "probable ID", was created by relaxing the cut off in IQ scores to be less than 85. An indicator variable for known causes of ID was also created to aid in aetiological studies where ID with a known cause may need to be excluded. Results: 158 of 14,370 participants (1.10%) were indicated as having ID by two or more sources and 449 (3.12%) were indicated as having probable ID when the criteria for IQ scores was relaxed to less than 85. There were 476 participants (3.31%) with 1 or fewer sources of available information on ID; these participants had their multisource variable set to missing. The number of cases of ID with known cause was 31 (0.22% of the cohort, 19.6% of those with ID). Conclusions: The multisource variable of ID can be used in future analyses on ID in ALSPAC children.

Characterizing Genotypes and Phenotypes Associated with Dysfunction of Channel-Encoding Genes in a Cohort of Patients with Intellectual Disability.

Ion channel dysfunction in the brain can lead to impairment of neuronal membranes and generate several neurological diseases, especially neurodevelopmental disorders. In this study, we set out to delineate the genotype and phenotype spectrums of 14 Iranian patients from 7 families with intellectual disability (ID) and/or developmental delay (DD) in whom genetic mutations were identified by next-generation sequencing (NGS) in 7 channel-encoding genes: KCNJ10, KCNQ3, KCNK6, CACNA1C, CACNA1G, SCN8A, and GRIN2B. Moreover, the data of 340 previously fully reported ID and/or DD cases with a mutation in any of these seven genes were combined with our patients to clarify the genotype and phenotype spectrum in this group. In total, the most common phenotypes in 354 cases with ID/DD in whom mutation in any of these 7 channel-encoding genes was identified were as follows: ID (77.4%), seizure (69.8%), DD (59.8%), behavioral abnormality (29.9%), hypotonia (21.7%), speech disorder (21.5%), gait disturbance (20.9%), and ataxia (20.3%). Electroencephalography abnormality (33.9%) was the major brain imaging abnormality. The results of this study broaden the molecular spectrum of channel pathogenic variants associated with different clinical presentations in individuals with ID and/or DD.

Intellectual disability in the children of the Avon Longitudinal Study of Parents and Children (ALSPAC)

Background: Intellectual disability (ID) describes a neurodevelopmental condition involving impaired cognitive and functional ability. Here, we describe a multisource variable of ID using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Methods: The multisource indicator variable for ID was derived from i) IQ scores less than 70 measured at age 8 and at age 15, ii) free text fields from parent reported questionnaires, iii) school reported provision of educational services for individuals with a statement of special educational needs for cognitive impairments, iv) from relevant READ codes contained in GP records, iv) international classification of disease diagnoses contained in electronic hospital records and hospital episode statistics and v) recorded interactions with mental health services for ID contained within the mental health services data set. A case of ID was identified if two or more sources indicated ID. A second indicator, labelled as “probable ID”, was created by relaxing the cut off in IQ scores to be less than 85. An indicator variable for known causes of ID was also created to aid in aetiological studies where ID with a known cause may need to be excluded. Results: 158 of 14,370 participants (1.10%) were indicated as having ID by two or more sources and 449 (3.12%) were indicated as having probable ID when the criteria for IQ scores was relaxed to less than 85. There were 476 participants (3.31%) with 1 or fewer sources of available information on ID; these participants had their multisource variable set to missing. The number of cases of ID with known cause was 31 (0.22%). Conclusions: The multisource variable of ID can be used in future analyses on ID in ALSPAC children.

Gestational age and risk of intellectual disability: a population-based cohort study

ObjectiveTo examine the association between gestational age at birth and risk of clinically diagnosed intellectual disability (ID) week by week to provide a detailed description of ID risk across the...

Autosomal dominant intellectual disability associated with the MED13L gene

Intellectual disability is a widespread group of diseases with population frequency 1–3%. More than half of intellectual disability cases are due to various genetic causes, including monogenic ones. The paper describes three clinical cases of MED13L-associated intellectual disability with an autosomal dominant inheritance. Novel probably pathogenic variants p.Cys118delinsTrpSer and p.Gln2111fs, as well as the previously described p.Pro866Leu mutation in the MED13L gene (NM_015335), were detected in patients by massive parallel sequencing. А rare familial case with two affected maternal half-siblings was of particular interest since the mutation detected in both children was not found in the mother (blood cells and buccal epithelium were investigated). We assume the presence of gonadal mosaicism in the mother, which allows to recommend families with confirmed cases of MED13L-associated intellectual disability to plan pregnancies with prenatal or preimplantational diagnostics. The disease has been shown to have a wide clinical variability, even intrafamilial.

Chorioamnionitis and risk of long-term neurodevelopmental disorders in offspring: a population-based cohort study

Evidence indicates that in utero exposure to chorioamnionitis might increase the risk of neurodevelopmental disorders in the offspring. However, findings on this topic have been inconsistent. To examine the association between chorioamnionitis and neurodevelopmental disorders in offspring. This was a retrospective population-based cohort study in Sweden. A total of 2,228,280 singleton live births and stillbirths between 1998 and 2019 were included in our study population. Data on maternal characteristics and neurodevelopmental disorders in offspring were obtained by individual record-linkages of nationwide Swedish registries. Chorioamnionitis was identified using the National Medical Birth Register. Inpatient and outpatient diagnoses were obtained for cerebral palsy, autism, attention deficit hyperactivity disorder, epilepsy, and intellectual disability. Multivariable Cox proportional hazards regression was used to estimate the association between chorioamnionitis and each neurodevelopmental disorder with adjusted hazard ratios and 95% confidence intervals. A causal mediation analysis of the relationship between chorioamnionitis and neurodevelopmental disorders with preterm delivery (<37 weeks) was performed. A total of 5770 (0.26%) offspring were exposed to chorioamnionitis during pregnancy. During the study's follow-up time there were 4752 (0.21%) cases of cerebral palsy, 17,897 (0.80 %) cases of epilepsy, 50,570 (2.27 %) cases of autism, 114,087 (5.12%) cases of attention deficit hyperactivity disorder, and 14,574 (0.65%) cases of intellectual disability. After adjusting for potential confounders, exposure to chorioamnionitis increased the hazard ratios of cerebral palsy (adjusted hazard ratio, 7.43; 95% confidence interval, 5.90-9.37), autism (adjusted hazard ratio, 1.43; 95% confidence interval, 1.21-1.68), attention deficit hyperactivity disorder (adjusted hazard ratio, 1.17; 95% confidence interval, 1.03-1.33), and intellectual disability (adjusted hazard ratio, 1.99; 95% confidence interval, 1.53-2.58), whereas chorioamnionitis was not significantly associated with higher rates of epilepsy in offspring. Mediation analysis revealed that these associations were mainly explained through preterm delivery; however, increased risk was also observed among term infants. Chorioamnionitis increases the risk of neurodevelopmental disorders, particularly cerebral palsy, autism, attention deficit hyperactivity disorder, and intellectual disability. These associations were mainly mediated through preterm delivery. Efforts for timely identification and appropriate interventions to treat infections during pregnancy will have sustained benefits in reducing the burden of neurologic complications in children at the population level.

Melanoma and intellectual disability: do prognostic factors at diagnosis differ from general population?

Few melanoma cases are reported in individuals with intellectual disability (ID), and prognostic factors at diagnosis are unknown in this population. This work was designed to investigate whether prognostic factors at diagnostic are different in patients with ID compared with a general population. Melanoma cases retrieved from Hérault's Tumour Registry (HTR) from 1995 to 2015 were cross-referenced against a list of adult patients with ID, living in Hérault. Major prognostic factors were compared with those in non-ID melanoma patients included in HTR and in patients followed by Montpellier University Hospital and included in the Réseau pour la Recherche et l'Investigation Clinique sur le Mélanome (RIC-Mel) database. Ten melanoma cases in individuals with ID were identified and compared with 3804 non-ID melanoma cases in HTR and 1024 non-ID melanoma cases included in RIC-Mel. Mean Breslow thickness at diagnosis was 4.6mm in melanoma cases among those with ID versus 1.89mm in HTR (P=0.109) and 2.36mm in RIC-Mel (P=0.156). Stage at diagnosis was superior to stage IIB in 42.9% of ID cases versus 11.4% of non-ID cases in HTR (P<0.05) and 8.5% in RIC-Mel (P<0.05). Melanomas in patients with ID had less favourable prognostic factors at diagnosis, including higher Breslow thickness and more advanced stage, than melanomas in non-ID patients. These adverse prognostic factors indicate a later diagnosis in this population, leading to a poorer prognosis. This work underlines the need to improve melanoma screening among individuals with ID.

Epilepsy and other phenotypic features of X-linked intellectual disability caused by the mutations in the KIAA2022 gene

To study the literature data and a series of our cases regarding the epilepsy clinic, electroencephalographic changes and other phenotypic features in X-linked intellectual disability (ID) caused by KIAA2022 mutations. We analyzed the anamnesis of the disease, using medical records from different Russian medical organizations, as well as the results of the genealogical anamnesis, clinical, genetic, electroencephalographic (EEG) and neuroimaging (brain MRI ) examinations of 7 patients (5 girls and 2 boys aged 5 to 13 years) with a confirmed diagnosis of X-linked ID caused by KIAA2022 mutations, in whom the clinical picture of the underlying disease was combined with epilepsy. The main common phenotypic features of patients with X-linked ID caused by the KIAA2022 mutations are mental retardation, lack of phrasal speech, motor developmental delay, and dysmorphism. The prominent epilepsy characteristics are myoclonic, atonic seizures with nods, flinches, body propulsions, atypical absences, and diffuse discharges «spike-polyspike-slow wave» on the EEG. No pathognomonic brain changes were found on MRI. In many cases, the absence of the effect of antiepileptic therapy was noted. The described cases of X-linked ID in combination with epilepsy show that this disease can be seen in males as well as in females, epilepsy is rather characterized by generalized seizures, and it is pharmacoresistant in many cases. There is a need for further research on this rare genetic syndrome.

Urine Organic Acids as Metabolic Indicators for Global Developmental Delay/Intellectual Disability in Chinese Children.

Objective: The purpose of this study was to search for differential metabolites in urine organic acids, and to characterize metabolic features that can be used to identify metabolites for exploration of global developmental delay (GDD)/intellectual disability (ID) etiology and pathogenesis. Methods: We screened positive test results that could explain GDD/ID from 1,253 cases, and the major differential metabolites in 132 urine organic acids from the 1,230 cases with negative results (863 GDD cases, 367 ID cases), and 100 typically developing children (TD). Non-supervisory principal component analysis and orthogonal partial least squares discriminant analysis were used to develop models to distinguish GDD/ID from TD children, and to detect major differential metabolites. Results: We get 23 positive results that could identify the cause of GDD/ID from 1253 cases diagnosed with GDD/ID. Among 1,230 negative results, we get the differential metabolites of the GDD group and the ID group had the same trend compared with the TD group. Twenty four differential metabolites were obtained from the GDD group, and 25 from the ID group (VIP > 1.0, p < 0.01). These differential metabolites were mainly related to the following pathways: the synthesis and degradation of ketone bodies, citrate cycle, alanine, aspartate and glutamate metabolism, pyrimidine metabolism, butanoate metabolism, pyruvate metabolism, fatty acid biosynthesis, valine, leucine and isoleucine degradation. Conclusion: The use of metabolomics research methods to detect urine organic acids of children with GDD/ID can discover differential metabolites, which might be valuable for future research on the etiology, pathogenesis, prognosis and possible interventions of GDD/ID. The significantly altered differential metabolites indicators could therefore be potential diagnostic biomarkers for GDD/ID.

WDR13: A Novel Gene Implicated in Non-Syndromic Intellectual Disability.

Investigating novel genetic variants involved in intellectual disability (ID) development is essential. X-linked intellectual disability (XLID) accounts for over 10% of all cases of ID in males. XLID genes are involved in many cellular pathways and processes. Some of them are not specific to the development and functioning of the neural system. The implementation of exome sequencing simplifies the search for novel variants, especially those less expected. Here, we describe a nonsense variant of the XLID gene, WDR13. The mutation c.757C>T (p.Arg253Ter) was uncovered by X-chromosome exome sequencing in males with a familial form of intellectual disability. Quantitative PCR (qPCR) analysis showed that variant c.757C>T caused a significant decrease in WDR13 expression in the patient's fibroblast. Moreover, it dysregulated other genes linked to intellectual disability, such as FMR1, SYN1, CAMK2A, and THOC2. The obtained results indicate the pathogenic nature of the detected variant and suggest that the WDR13 gene interacts with other genes essential for the functioning of the nervous system, especially the synaptic plasticity process.

A Tiered Genetic Screening Strategy for the Molecular Diagnosis of Intellectual Disability in Chinese Patients.

Objective: Intellectual disability (ID) is one of the most common developmental disabilities. To identify the genetic etiology of IDs in Chongqing, we conducted a multistage study in Chinese Han patients. Methods: We collected the clinical and etiological data of 1665 ID patients, including 1,604 from the disabled children evaluation center and 61 from the pediatric rehabilitation unit. Routine genetic screening results were obtained, including karyotype and candidate gene analysis. Then 105 idiopathic cases with syndromic and severe ID/developmental delay (DD) were selected and tested by chromosomal microarray (CMA) and whole exome sequencing (WES) sequentially. The pathogenicity of the CNVs and SNVs were evaluated according to ACMG guidelines. Results: Molecular diagnosis was made by routine genetic screening in 216 patients, including 196 chromosomal syndromes. Among the 105 idiopathic patients, 49 patients with pathogenic/likely pathogenic CNVs and 21 patients with VUS were identified by CMA. Twenty-six pathogenic CNVs underlying well-known syndromic cases, such as Williams-Beuren syndrome, were confirmed by multiplex ligation-dependent probe amplification (MLPA). Nine novel mutations were identified by WES in thirty-fix CNV-negative ID cases. Conclusions: The study illustrated the genetic aberrations distribution of a large ID cohort in Chongqing. Compared with conventional or single methods, a tiered high-throughput diagnostic strategy was developed to greatly improve the diagnostic yields and extend the variation spectrum for idiopathic syndromic ID cases.

Is the Intellectual Functioning Component of AAIDD's 12th Manual Satisficing?

Is the Intellectual Functioning Component of AAIDD's 12th Manual Satisficing?

Investigating the Characteristics of Intelligence Quotient in Individuals with Intellectual Disability in Rafsanjan, 2019

Background: Comprehensive and reliable information about intellectual disability (ID) and its association with environmental and demographic variables is scarce. Objectives: This study aimed to investigate the characteristics of intelligence quotient (IQ) in children with ID. Methods: In this descriptive cross-sectional study, all children with ID under the care of the welfare organization and special needs schools of the city of Rafsanjan were included in the study by census sampling (n = 207). After obtaining informed consent, parents completed a checklist including participants’ age, gender, birth month, birth season, and birth order, and also parents’ age and education level. Data were analyzed by one-way ANOVA and chi-square tests. Results: Out of 207 children, 107 (51.7%) were male, 100 (48.3%) were female, 36.2% were first-born, 14.5% were born in May, and 5.3% were born in March (the most-the least). The relationship of IQ to birth season and month was not significant (P &gt; 0.05). Among the children, 39.6% were offspring of consanguineous marriages, but no significant relationship was observed between their IQ and consanguineous marriages (P &gt; 0.05). The level of ID was correlated with parents’ age (P &lt; 0.05). A significant relationship was also found between IQ and the number of offspring (P = 0.004). All cases of severe ID were seen in girls and a significant relationship was detected between IQ and gender (P = 0.0001). Conclusions: Individuals with ID have an IQ below 70. ID in children was correlated with the parents’ old age and low education level, but not with their birth season. However, given the higher prevalence of infectious diseases especially viral infections in cold months, it is only sensible to educate couples about how to protect the health of mother and fetus during these periods.

Rates of protein synthesis are reduced in peripheral blood mononuclear cells (PBMCs) from fragile X individuals.

BackgroundFragile X syndrome (FXS) is the leading inherited cause of intellectual disability and is caused by the loss of expression of the Fragile X mental retardation protein (FMRP). In animal model of FXS, the absence of FMRP leads to an aberrant rate of neuronal protein synthesis, which in turn is believed to be at the origin of defects regarding spine morphology and synaptic plasticity. Normalisation of protein synthesis in these models has been associated with a rescue of FXS behavioral and biochemicals phenotype, thus establishing the rate of protein synthesis as one of the most promising monitoring biomarker for FXS. However, rate of protein synthesis alteration in fragile X individuals is not well characterized.MethodWe applied a robust radiolabeled assay to measure rate of protein synthesis in freshly extracted peripheral blood mononuclear cells (PBMCs) and blood platelets. We ultimately settle on PBMCs to measure and compare rate of protein synthesis in 13 males with fragile X and 14 matched controls individuals.ResultsUsing this method, we measured a 26.9% decrease (p = 0,0193) in the rate of protein synthesis in fragile X individuals PBMCs. Furthermore, the rate of protein synthesis measurements obtained were highly reproducible, highlighting the robustness of the method.ConclusionOur work presents the first evidence of a diminution of the rate of protein synthesis in a human peripheral model of fragile X. Our results also support the finding of previous studies using brain PET imaging in Fragile X individuals. Since our assay only requires a simple venous puncture, it could be used in other cases of intellectual disability in order to determine if an aberrant rate of protein synthesis is a common general mechanism leading to impairment in synaptic plasticity and to intellectual disability.

Risk of intellectual disability and maternal history of spontaneous abortion: a nationwide cohort study.

To investigate the association between a maternal history of spontaneous abortion and intellectual disability in children. This cohort study included 1778786 children (913 340 males, 865 085 females, 361 missing data; mean age 15y 2mo, SD 8y 11mo, range birth to 40y) born in Denmark between 1977 and 2016. Cox proportional hazard regression was used to estimate the hazard ratios (HRs) of intellectual disability. The overall HR of intellectual disability for children with a maternal history of spontaneous abortion was 1.17 (95% confidence interval [CI] 1.12-1.22) and the risk for multiple spontaneous abortions (HR=1.30, 95% CI 1.20-1.40) was higher than for a single spontaneous abortion (HR=1.13, 95% CI 1.07-1.18). When only cases of inpatient intellectual disability were included, the estimates increased slightly: the overall HR was 1.22 (95% CI 1.12-1.32), the HR for multiple spontaneous abortions was 1.37 (95% CI 1.20-1.58), and the HR for a single spontaneous abortion was 1.17 (95% CI 1.07-1.28). The risks were similar regardless of whether spontaneous abortion occurred before or after the index delivery. Estimates were nearly unchanged after adjusting for preterm birth, low birthweight, or Apgar score. Children born to mothers with spontaneous abortion, especially multiple spontaneous abortions, may be at a higher risk of intellectual disability in later life, regardless of whether spontaneous abortion occurred before or after the index delivery. The findings have clinical implications for targeted early intervention of children with intellectual disability. What this paper adds A maternal history of spontaneous abortion was associated with a risk of intellectual disability in offspring. The risk was higher in children whose mothers previously had multiple spontaneous abortions. Similar risks were observed regardless of whether spontaneous abortion occurred before or after childbirth.

Review On Clinical And Molecular Genetics Of Autosomal Recessive Intellectual Disability

Intellectual disability (ID) is a relatively common phenotype with multiple etiologies. Recent progress in the genetics of ID greatly expanded our understanding of the biological defects underlying this clinical entity. While most published cohort genetic studies on ID revealed the important contribution of de novo (germline or postzygotic) variants, we focused in this study of autosomal recessive ID (ARID), that account for most of the molecular bases in ID cases in inbred populations. We discussed the current state of ARID from a clinical, molecular and genetics standpoints.

Two Cases of Recessive Intellectual Disability Caused by NDST1 and METTL23 Variants

Intellectual disability (ID) is a highly heterogeneous genetic condition with more than a thousand genes described so far. By exome sequencing of two consanguineous families presenting hallmark features of ID, we identified two homozygous variants in two genes previously associated with autosomal recessive ID: NDST1 (c.1966G>A; p.Asp656Asn) and METTL23 (c.310T>C; p.Phe104Leu). The segregation of the variants was validated by Sanger sequencing in all family members. In silico homology modeling of wild-type and mutated proteins revealed substantial changes in the secondary structure of both proteins, indicating a possible effect on function. The identification and validation of new pathogenic NDST1 and METTL23 variants in two cases of autosomal recessive ID further highlight the importance of these genes in proper brain function and development.