Etiology Of Intellectual Disability Research Articles

Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders.

Most people with intellectual disability (ID) do not receive a molecular diagnosis following genetic testing. To identify new etiologies of ID, we performed a genetic association analysis comparing the burden of rare variants in 41,132 noncoding genes between 5,529 unrelated cases and 46,401 unrelated controls. RNU4-2, which encodes U4 small nuclear RNA, a critical component of the spliceosome, was the most strongly associated gene. We implicated de novo variants among 47 cases in two regions of RNU4-2 in the etiology of a syndrome characterized by ID, microcephaly, short stature, hypotonia, seizures and motor delay. We replicated this finding in three collections, bringing the number of unrelated cases to 73. Analysis of national genomic diagnostic data showed RNU4-2 to be a more common etiological gene for neurodevelopmental abnormality than any previously reported autosomal gene. Our findings add to the growing evidence of spliceosome dysfunction in the etiologies of neurological disorders.

Insights of Dementia in Persons With Intellectual Disability

Intellectual disability and dementia are age-dependent terms for a cognitive impair occurring during developmental age and in adulthood, respectively. Intellectually disabled people like any other people may develop dementia in adulthood. Thus, clinicians should learn to differentiate dementia-indicating signs from intellectual disability related cognitive deficiencies for an early diagnosis and treatment onwards. In intellectual disability, intellectual and adaptive skills of an individual are two standard deviations below the expected age-matched population, and dementia is characterized by a progressive cognitive decline. The cause of both disorders can be genetic, acquired or multifactorial. An increased risk of Alzheimer's disease in Down syndrome is well known unlike the development of dementia in other intellectual disability syndromes. This commentary discusses 1) how the dementia indicating signs present in intellectually disabled persons, 2) why it is important to distinguish dementia (and its causes) from intellectual disability and 3) why it is important to know the etiology of intellectual disability

Intellectual disabilities and autism among children with congenital heart defects, Western Australia, 1983–2010

BackgroundChildren with congenital heart defects (CHDs) are at higher risk of developing an intellectual disability. However, severity of intellectual disabilities among this group of children are largely unknown. Our objective was to determine the risk of intellectual disability (ID), ID severity, and autism among children with CHDs.MethodsWe conducted a retrospective cohort study of singleton live births in Western Australia (n = 20,592) between 1983 and 2010. Children with CHDs were identified from the Western Australian Register for Developmental Anomalies (n = 6563) and infants without CHDs were randomly selected from state birth records (n = 14,029). Children diagnosed with ID before 18 years were identified by linkage to statewide Intellectual Disability Exploring Answers database. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from logistic regression models for all CHDs combined and by CHD severity adjusting for potential confounders.ResultsOf 20,592 children, 466 (7.1%) with CHDs and 187 (1.3%) without CHDs had an ID. Compared to children without CHDs, children with any CHD had 5.26 times (95% CI 4.42, 6.26) the odds of having an ID and 4.76 times (95% CI 3.98, 5.70) the odds of having mild/moderate ID. Children with any CHD had 1.76 times the odds of having autism (95% CI 1.07, 2.88), and 3.27 times the odds of having an unknown cause of ID (95% CI 2.65, 4.05) compared to children without CHD. The risk of having autism (aOR 3.23, 95% CI 1.11, 9.38), and unknown cause of ID (aOR 3.45, 95% CI 2.09, 5.70) was greatest for children with mild CHD.ConclusionsChildren with CHDs were more likely to have an ID or autism. Future research should elucidate underlying etiology of ID in children with CHDs.

Regulatory de novo mutations underlying intellectual disability.

The genetic aetiology of a major fraction of patients with intellectual disability (ID) remains unknown. De novo mutations (DNMs) in protein-coding genes explain up to 40% of cases, but the potential role of regulatory DNMs is still poorly understood. We sequenced 63 whole genomes from 21 ID probands and their unaffected parents. In addition, we analysed 30 previously sequenced genomes from exome-negative ID probands. We found that regulatory DNMs were selectively enriched in fetal brain-specific enhancers as compared with adult brain enhancers. DNM-containing enhancers were associated with genes that show preferential expression in the prefrontal cortex. Furthermore, we identified recurrently mutated enhancer clusters that regulate genes involved in nervous system development (CSMD1, OLFM1, and POU3F3). Most of the DNMs from ID probands showed allele-specific enhancer activity when tested using luciferase assay. Using CRISPR-mediated mutation and editing of epigenomic marks, we show that DNMs at regulatory elements affect the expression of putative target genes. Our results, therefore, provide new evidence to indicate that DNMs in fetal brain-specific enhancers play an essential role in the aetiology of ID.

Facilitating Digital Empowerment for Intelligent Cares in Mountain Region

Intellectual disability and dementia are age-dependent terms for a cognitive impair occurring during developmental age and in adulthood, respectively. Intellectually disabled people like any other people may develop dementia in adulthood. Thus, clinicians should learn to differentiate dementia-indicating signs from intellectual disability related cognitive deficiencies for an early diagnosis and treatment onwards. In intellectual disability, intellectual and adaptive skills of an individual are two standard deviations below the expected age-matched population, and dementia is characterized by a progressive cognitive decline. The cause of both disorders can be genetic, acquired or multifactorial. An increased risk of Alzheimer's disease in Down syndrome is well known unlike the development of dementia in other intellectual disability syndromes. This commentary discusses 1) how the dementia indicating signs present in intellectually disabled persons, 2) why it is important to distinguish dementia (and its causes) from intellectual disability and 3) why it is important to know the etiology of intellectual disability.

Insights of Dementia in Persons with Intellectual Disability

Intellectual disability and dementia are age-dependent terms for a cognitive impair occurring during developmental age and in adulthood, respectively. Intellectually disabled people like any other people may develop dementia in adulthood. Thus, clinicians should learn to differentiate dementia-indicating signs from intellectual disability related cognitive deficiencies for an early diagnosis and treatment onwards. In intellectual disability, intellectual and adaptive skills of an individual are two standard deviations below the expected age-matched population, and dementia is characterized by a progressive cognitive decline. The cause of both disorders can be genetic, acquired or multifactorial. An increased risk of Alzheimer's disease in Down syndrome is well known unlike the development of dementia in other intellectual disability syndromes. This commentary discusses 1) how the dementia indicating signs present in intellectually disabled persons, 2) why it is important to distinguish dementia (and its causes) from intellectual disability and 3) why it is important to know the etiology of intellectual disability.

Identifying Genetic Etiology in Patients with Intellectual Disability: An Experience in Public Health Services in Northeastern Brazil.

Intellectual disability (ID) is considered a common neuropsychiatric disorder that affects up to 3% of the population. The etiologic origin of ID may be genetic, environmental, and multifactorial. Chromosomopathies are relatively common among the genetic causes of ID, especially in the most severe cases and those associated with dysmorphic features. Currently, the application of new molecular cytogenetics technologies has increasingly allowed the identification of microdeletions, microduplications, and unbalanced translocations as causes of ID. The objective of this study was to investigate the etiology of ID in patients admitted to a public hospital in Northeastern Brazil. In total, 119 patients with ID who had normal karyotypes and fragile X exams participated in this study. The patients were initially physically examined for microdeletion syndromes and then tested using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), methylation-sensitive polymerase chain reaction (MS-PCR), and chromosome microarray analysis (CMA), according to clinical suspicion. Patients with no diagnoses after FISH, MLPA, and/or MS-PCR evaluations were subsequently tested by CMA. The rate of etiologic diagnoses of ID in the current study was 28%. FISH diagnosed 25 out of 79 tested (31%), MLPA diagnosed 26 out of 79 tested (32%), MS-PCR diagnosed 7 out of 20 tested (35%), and the single nucleotide polymorphism array diagnosed 6 out of 27 tested (22%). Although the CMA is the most complete and recommended tool for the diagnosis of microdeletions, microduplications, and unbalance translocations in patients with ID, FISH, MLPA, and MS-PCR testing can be used as the first tests for specific syndromes, as long as the patients are first physically screened clinically, especially in the public health networks system in Brazil, where resources are scarce.

Genetic etiology of adult intellectual disability (ID) of unknown cause in Qatar: a retrospective study.

Background: Intellectual disability (ID) is a common condition that consists of a heterogeneous group of clinical conditions with different etiologies, including genetic conditions. Identifying those with a genetic cause results in better clinical management.Aim: To identify the genetic etiology of ID in adult patients with unknown etiology presenting to a specialist learning disability service in Qatar.Methods: Retrospective review of chart notes of patients referred for ID service from January 1, 2015 to January 1, 2020.Results: Of the 228 patients, 82 had a known cause of ID and did not require genetic testing, 22 had an unknown cause and underwent genetic testing, and 124 had an unknown cause and did not undergo genetic testing. Of the 82 patients with a known cause of ID, about one-half had an autistic spectrum disorder (ASD) and 18 patients had a genetic disorder. Of the 22 patients who underwent genetic testing, 2 were positive for the Fragile-X mental retardation 1 gene, 3 underwent chromosomal microarray, and 7 underwent whole-exome sequencing. Seven abnormal genes were identified.Conclusions: Identifying the underlying genetic etiology of patients with ID has major implications for diagnostic and therapeutic approaches. Additionally, it guides a prediction of the natural history of the disease and makes it possible to test at-risk family members.

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.

Altered Gene Expression Profiles in Neural Stem Cells Derived from Duchenne Muscular Dystrophy Patients with Intellectual Disability.

Intellectual disability (ID) is a neurodevelopmental disorder defined by below-average intelligence (intelligence quotient of <70) accompanied by adaptive behavior deficits. Defects in the functions of neural stem cells during brain development are closely linked to the pathogenesis of ID. To understand the molecular etiology of ID, we examined neural stem cells from individuals with Duchenne muscular dystrophy (DMD), a genetic disorder in which approximately one-third of the patients exhibit ID. In this study, we generated induced pluripotent stem cells from peripheral blood mononuclear cells from a normal individual and DMD patients with and without ID to identify ID-specific functional and molecular abnormalities. We found defects in neural ectoderm formation in the group of DMD patients with ID. Our transcriptome analysis of patient-derived neural stem cells revealed altered expression of genes related to the hippo signaling pathway and neuroactive ligand-receptor interaction, implicating these in the pathogenesis of ID in patients with DMD.

Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations.

Intellectual disability (ID) and autism spectrum disorder (ASD) belong to neurodevelopmental disorders and occur in ~1% of the general population. Due to disease heterogeneity, identifying the etiology of ID and ASD remains challenging. Exome sequencing (ES) offers the opportunity to rapidly identify variants associated with these two entities that often co-exist. Here, we performed ES in a cohort of 200 patients: 84 with isolated ID and 116 with ID and ASD. We identified 41 pathogenic variants with a detection rate of 22% (43/200): 39% in ID patients (33/84) and 9% in ID/ASD patients (10/116). Most of the causative genes are genes responsible for well-established genetic syndromes that have not been recognized for atypical phenotypic presentations. Two genes emerged as new candidates: CACNA2D1 and GPR14. In conclusion, this study reinforces the importance of ES in the diagnosis of ID/ASD and underlines that “reverse phenotyping” is fundamental to enlarge the phenotypic spectra associated with specific genes.

A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line.

Assessment of changing trends of risk factors contributing to Intellectual Disability – A retrospective study

The etiology of Intellectual Disability is varied and difficult to establish. Reports from India on the spectrum of underlying causative factors are lacking. So this retrospective study was conducted to identify the various etiologies of Intellectual Disability (ID). Study was conducted at a tertiary care center. The etiology of ID was ascertained after clinical assessment. Two groups were ascertained Group A those who were born in 2000 and before and group B those who were born in 2001 and after. The spectrum of causative conditions was identified.In both groups the prevalence of ID was higher among males than in females. No major difference in domicile was noted. More than 75% children were off springs of non-consanguineous parents. Most of them belong to mild ID (45%) in both groups. The etiological yield was 18.33% in group A and 11.66% in group B with Prenatal cause, followed by perinatal 48.33% in group A and 55% in group B, being the most common and postnatal cause 8.33% and 5% in group A and B respectively .Idiopathic causes constitute 20% in group A and 25% in group B, Few cases fall under multiple etiologies. It is possible to ascertain the diagnosis in most of the cases of intellectual disability. The prenatal and postnatal causes are decreasing due to awareness of Antenatal checkup, and active treatment respectively. But the Perinatal cause, which is preventable one, is increasing, which needs active intervention; also idiopathic cause which needs thorough screening.

Whole genome sequencing of 45 Japanese patients with intellectual disability.

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single‐step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.

Etiology of intellectual disability in individuals from special education schools in the south of Brazil

BackgroundIntellectual Disability (ID) is characterized by significant limitations that affect intellectual functioning, adaptive behavior, and practical skills which directly interfere with interpersonal relationships and the environment. In Western countries, individuals with ID are overrepresented in the health system, often due to associated comorbidities, and its life-time cost places ID as one of the most expensive conditions of all diagnoses in the International Classification of Diseases. Most of the people affected (75%) live in low-income countries, suffer from malnutrition, lack health care, and do not have access to adequate treatment. The aim of this study was to obtain an estimate of the diagnostic status as well as the prevalence of familial ID among individuals with serious (moderate or severe) ID in a region of the State of Santa Catarina, investigating attendees of special education schools of the Florianópolis Macroregion.MethodsThis was a cross-sectional study conducted between August 2011 and August 2014, through a semi-structured screening questionnaire for the collection of relevant developmental, clinical, familial and educational data, applied in an interview to guardians of students of special education schools of the macroregion of Florianópolis.ResultsThe participant special schools enrolled close to 1700 students during the study period and the questionnaire was applied to 849 (50.5%). The male to female ratio of the participants was 1.39:1. Clear etiologic explanations were relatively scarce (24%); most diagnoses referring only to the type and the degree of impairment and for the majority (61.4%) the cause was unknown. About half were sporadic cases within their families (considering three generations). For 44.2% at least one other case of an ID-related condition in the extended family was mentioned, with 293 (34.5%) representing potential familial cases.ConclusionHere we describe the epidemiological profile, the available diagnostics, etiology, family history and possible parental consanguinity of participants with ID of special education schools in the South of Brazil. The main results show the need for etiological diagnosis and uncover the relevance of potential hereditary cases in a population where consanguineous unions have a relatively low frequency (0,6%) and highlight the need for public health actions.

Migration or ethnic minority status and risk of autism spectrum disorders and intellectual disability: systematic review.

BackgroundThere is an emerging evidence that the migration and the ethnic minority status are associated with the risks of autism spectrum disorder (ASD) and intellectual disability (ID). This systematic review aimed to investigate whether associations are specific to ASD or ID; whether and which migration-related or ethnically determined factors are associated with the risk of ASD and ID; and what mechanisms may explain these risks.MethodsA systematic literature search was conducted using Embase, Medline and PsycINFO for studies reporting on the risks of ASD and/or ID among migrants, descendants of migrants and/or ethnic minorities. Risks of any ASD, ASD + ID, ASD – ID and any ID were reviewed in relation to migration and ethnic minority status, with consideration to the study quality. In addition, possible underlying mechanisms suggested in the included studies were summarized.ResultsThirty-five studies were included. The summarized evidence indicated an increased risk of ASD + ID and a decreased risk of ASD – ID in migrants, descendants of migrants and ethnic minorities. These associations appeared more pronounced among children of migrant mothers, with origin in low-income countries, and among descendants of migrants. Data on ID were scarce. Suggested mechanisms explaining the increased risks of ASD + ID included environmental factors acting in utero and genetic factors (including consanguinity), while ascertainment bias was proposed to account for the lowered risks of diagnosed ASD – ID.ConclusionMigration-related factors acting in utero and/or associated with origin in low-income countries may be important in the ASD + ID aetiology, although further confirmative studies are needed.

Study of the MDM2 -410T-G polymorphism (rs2279744) by pyrosequencing in mothers of Down Syndrome subjects.

Trisomy 21 or Down syndrome (DS) is the most frequent genetic etiology of intellectual disability in humans. MDM2 gene expression has a potential role as a risk factor for human aneuploidy. -410T-G (rs2279744) functional polymorphism in MDM2 gene impacts on the mechanisms of chromosomal non-disjunction. We analyzed, within a case-control study, such polymorphism in mothers of subjects with DS. Nucleotide polymorphism was detected by pyrosequencing technology. The distribution of MDM2-410T-G polymorphism showed no significant difference among mothers of subjects with DS and controls. Our results suggest that MDM2 -410T-G polymorphism is not a risk factor for DS in mothers.

Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual Disability and Microcephaly

Intellectual disability (ID) is a genetically and clinically heterogeneous disorder, characterized by limited cognitive abilities and impaired adaptive behaviors. In recent years, exome sequencing (ES) has been instrumental in deciphering the genetic etiology of ID. Here, through ES of a large cohort of individuals with ID, we identified two bi-allelic frameshift variants in METTL5, c.344_345delGA (p.Arg115Asnfs∗19) and c.571_572delAA (p.Lys191Valfs∗10), in families of Pakistani and Yemenite origin. Both of these variants were segregating with moderate to severe ID, microcephaly, and various facial dysmorphisms, in an autosomal-recessive fashion. METTL5 is a member of the methyltransferase-like protein family, which encompasses proteins with a seven-beta-strand methyltransferase domain. We found METTL5 expression in various substructures of rodent and human brains and METTL5 protein to be enriched in the nucleus and synapses of the hippocampal neurons. Functional studies of these truncating variants in transiently transfected orthologous cells and cultured hippocampal rat neurons revealed no effect on the localization of METTL5 but alter its level of expression. Our in silico analysis and 3D modeling simulation predict disruption of METTL5 function by both variants. Finally, mettl5 knockdown in zebrafish resulted in microcephaly, recapitulating the human phenotype. This study provides evidence that biallelic variants in METTL5 cause ID and microcephaly in humans and highlights the essential role of METTL5 in brain development and neuronal function.

Genomic imbalances defining novel intellectual disability associated loci

BackgroundHigh resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID).ResultsWe have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed.ConclusionsIdentification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.

Whole-Transcriptome Analysis Reveals Dysregulation of Actin-Cytoskeleton Pathway in Intellectual Disability Patients

A significant level of genetic heterogeneity has been demonstrated in intellectual disability (ID). More than 700 genes have been identified in ID patients. To identify molecular pathways underlying this heterogeneity, we applied whole-transcriptome analysis using RNA-Seq in consanguineous families with ID. Significant changes in expression of genes related to neuronal and actin cytoskeletal functions were observed in all the ID families. Remarkably, we found a significant down-regulation of SHTN1 gene and up-regulation of FGFR2 gene in all ID patients. FGFR2, but not SHTN1, was previously reported as an ID causing gene. Detailed gene ontology analyses identified pathways linked to tyrosine protein kinase, actin cytoskeleton, and axonogenesis to be affected in ID patients. The findings reported here provide new insights into the candidate genes and molecular pathways underling ID and highlight the key role of actin cytoskeleton in etiology of ID.