In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. ...Because of the high rate of parental consanguinity, which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in near‐ and middle‐east countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but because of the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole‐exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant DNMs. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6‐fold, and about 4.1 to 4.25‐fold for children of first‐cousin unions. These results do not rhyme with recent opinions that consanguinity‐related health risks are generally small and have been “overstated” in the past.
Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences.
We collected the ...data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms.
IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments.
This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.
The field of intellectual and developmental disabilities (IDD) is currently experiencing a significant transformation that encompasses an integrated approach, especially regarding shared aspects such ...as a focus on the human and legal rights, the eligibility for services and supports, and an emphasis on individualized supports provided within inclusive community-based environments. Accompanying this transformation is the increased need of precision in both the operational definitions of IDD-related constructs, and the terminology used to describe the respective construct.
the specialized literature was revised, and previous works on the subject by the authors were updated.
This article provides psychologists with the current definition of intellectual disability, operational definitions of intellectual disability and developmental disabilities constructs and associated terminology, and the parameters of an integrated approach to disability.
Implications for psychologists who are involved in diagnosis, classification, and planning supports for persons with intellectual or developmental disability are discussed.
Current global estimates suggest the proportion of the population with autism spectrum disorder (ASD) who have intellectual disability (ID) is approximately 50%. Our objective was to ascertain the ...existence of selection bias due to under-inclusion of populations with ID across all fields of autism research. A sub-goal was to evaluate inconsistencies in reporting of findings.
This review covers all original research published in 2016 in autism-specific journals with an impact factor greater than 3. Across 301 included studies, 100,245 participants had ASD. A random effects meta-analysis was used to estimate the proportion of participants without ID. Selection bias was defined as where more than 75% of participants did not have ID.
Meta-analysis estimated 94% of all participants identified as being on the autism spectrum in the studies reviewed did not have ID (95% CI 0.91-0.97). Eight out of ten studies demonstrated selection bias against participants with ID. The reporting of participant characteristics was generally poor: information about participants' intellectual ability was absent in 38% of studies (
= 114). Where there was selection bias on ID, only 31% of studies mentioned lack of generalisability as a limitation.
We found selection bias against ID throughout all fields of autism research. We recommend transparent reporting about ID and strategies for inclusion for this much marginalised group.
Intellectual disability (ID) can be caused by non-genetic and genetic factors, the latter being responsible for more than 1700 ID-related disorders. The broad ID phenotypic and genetic heterogeneity, ...as well as the difficulty in the establishment of the inheritance pattern, often result in a delay in the diagnosis. It has become apparent that massive parallel sequencing can overcome these difficulties. In this review we address: (i) ID genetic aetiology, (ii) clinical/medical settings testing, (iii) massive parallel sequencing, (iv) variant filtering and prioritization, (v) variant classification guidelines and functional studies, and (vi) ID diagnostic yield. Furthermore, the need for a constant update of the methodologies and functional tests, is essential. Thus, international collaborations, to gather expertise, data and resources through multidisciplinary contributions, are fundamental to keep track of the fast progress in ID gene discovery.
Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as ...proband-parent trios.
Whole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected).
Pathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected first-degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses, we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS and 4.7% of families with a negative result eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGaP.
Our data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.
Individuals with specific genetic syndromes associated with intellectual disability (ID), such as Williams syndrome (WS), are at increased risk for developing anxiety disorders. A systematic ...literature review identified sixteen WS papers that could generate pooled prevalence estimates of anxiety disorders for WS. A meta-analysis compared these estimates with prevalence estimates for the heterogeneous ID population and the general population. Estimated rates of anxiety disorders in WS were high. WS individuals were four times more likely to experience anxiety than individuals with ID, and the risk was also heightened compared to the general population. The results provide further evidence of an unusual profile of high anxiety in WS.
The current standard of care for diagnosis of severe intellectual disability (ID) and epileptic encephalopathy (EE) results in a diagnostic yield of ∼50%. Affected individuals nonetheless undergo ...multiple clinical evaluations and low‐yield laboratory tests often referred to as a ‘diagnostic odyssey’. This study was aimed at assessing the utility of clinical whole‐exome sequencing (WES) in individuals with undiagnosed and severe forms of ID and EE, and the feasibility of its implementation in routine practice by a small regional genetic center. We performed WES in a cohort of 43 unrelated individuals with undiagnosed ID and/or EE. All individuals had undergone multiple clinical evaluations and diagnostic tests over the years, with no definitive diagnosis. Sequencing data analysis and interpretation were carried out at the local molecular genetics laboratory. The diagnostic rate of WES reached 32.5% (14 out of 43 individuals). Genetic diagnosis had a direct impact on clinical management in four families, including a prenatal diagnostic test in one family. Our data emphasize the clinical utility and feasibility of WES in individuals with undiagnosed forms of ID and EE and highlight the necessity of close collaborations between ordering physicians, molecular geneticists, bioinformaticians and researchers for accurate data interpretation.
Individuals with intellectual and developmental disabilities (IDD) are at high risk of co-occurring mental health conditions, including major depressive disorder, bipolar disorder, anxiety disorders, ...psychotic illnesses, impulse control disorders, and others. Because of symptoms associated with these illnesses and with the disabilities themselves, these individuals are often served in a mental health service system framework. However, treatment for them in these settings has typically not been sufficiently nimble, knowledgeable, or adept. Most mental health professionals receive little training about the needs of this population, and system structures typically bifurcate care, when, in reality, conditions can be complex and overlapping. In this first of two articles on care for persons with IDD in the mental health system, the authors provide a clinical overview of these neurodevelopmental disorders and of mental health and other conditions that co-occur with IDD. Considerations and challenges for treating this population in the mental health system include early recognition of mental health conditions, which often requires caregiver and family input, as well as information from a variety of additional collateral sources; the importance of trauma-informed and person-centered care; the promotion of self-determination through use of decision supports; use of approaches such as applied behavior analysis to develop a frame to address challenging behaviors; and the need to properly assess and provide thoughtful pharmacologic intervention when appropriate. The ability of individuals with IDD to thrive in a wide range of community integration opportunities depends on many factors, and clinicians must understand and use the available approaches for treating them.
Bi‐allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical ...description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi‐allelic TECPR2‐variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross‐sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N‐ and C‐terminal regions containing β‐propeller repeats. Despite constituting nearly half of disease‐associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2‐associated disorder. This sets the stage for future prospective natural history studies.
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