Transition to adulthood for young people with intellectual disabilities and developmental disabilities (IDD) has been given significant attention in research, policy development and practice. The aim of this paper was to explore how a recently developed theoretical outcomes-based framework for measuring the quality of services for people with disabilities could potentially be useful in conceptualizing and supporting successful transition to adulthood. The theoretical discussion draws on both the scoping review and template analysis that was used to develop the Service Quality Framework and on a separate study synthesizing expert completed country templates and literature review which included models of and research on successful transition to adulthood. Synthesis identified that using a quality of life outcomes focused framework of Service Quality could be mapped onto and extend current thinking on what is seen as successful transition to adulthood by putting the focus on successful transition as people with IDD moving towards having similar opportunities and quality of life as other adults without disabilities living in the same community/society. Implications of a more wide-ranging definition and holistic view for both practice and future research are discussed.

• Klíčová slova
• education, intellectual and developmental disabilities, measurement, quality of life, quality of support services, transition,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Background: This protocol outlines research to explore family members' and paid staff's perceptions of the impact of COVID-19 on individuals with intellectual and developmental disabilities and their caregivers. Evidence suggests that people with intellectual and developmental disabilities experience disparities in healthcare access and utilisation. This disparity was evident early in the pandemic when discussions arose regarding the potential exclusion of this population to critical care. Methods: An anonymous online survey will be conducted with caregivers, both family members and paid staff, to explore their perceptions of the impact of COVID-19 in terms of demographics, living arrangements, access to services, social distancing, and carer wellbeing. The survey will be developed by the research team, many of whom are experts in intellectual disability within their own jurisdictions. Using back-translation our team will translate the survey for distribution in 18 countries worldwide for international comparison. The survey team have extensive personal and professional networks and will promote the survey widely on social media with the support of local disability and advocacy agencies. Statistical descriptive and comparative analyses will be conducted. Ethical approval has been obtained for this study from University College Dublin's Human Research Ethics Committee (HS-20-28-Linehan). Dissemination: Study findings will be prepared in a number of formats in order to meet the needs of different audiences. Outputs will include academic papers, lessons learned paper, practice guidelines, reports, infographics and video content. These outputs will be directed to families, frontline and management delivering disability services, national-level policy makers, healthcare quality and delivery authorities, national pandemic organisations and international bodies.

• Klíčová slova
• COVID-19, Caregivers Carers, Coronavirus, Health Disparity, Intellectual Disability, Intellectual and Developmental Disability, Pandemic,
• Publikační typ
• časopisecké články MeSH

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.

• MeSH
• Cercopithecus aethiops MeSH
• COS buňky MeSH
• dánio pruhované genetika   MeSH
• dítě MeSH
• HEK293 buňky MeSH
• lidé MeSH
• mentální retardace * genetika   MeSH
• mikrocefalie * genetika   patologie   MeSH
• myši MeSH
• neurony metabolismus   patologie   MeSH
• předškolní dítě MeSH
• proteiny asociované s mikrotubuly genetika   metabolismus   MeSH
• proteiny nervové tkáně genetika   metabolismus   MeSH
• vývojové poruchy u dětí * genetika   MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• NAV3 protein, human MeSH Prohlížeč
• proteiny asociované s mikrotubuly MeSH
• proteiny nervové tkáně MeSH

BACKGROUND: Chromosomal microarray analysis has been shown to be a valuable and cost effective assay for elucidating copy number variants (CNVs) in children with intellectual disability and developmental delay (ID/DD). METHODS: In our study, we performed array-based comparative genomic hybridization (array-CGH) analysis using oligonucleotide-based platforms in 542 Czech patients with ID/DD, autism spectrum disorders and multiple congenital abnormalities. Prior to the array-CGH analysis, all the patients were first examined karyotypically using G-banding. The presence of CNVs and their putative derivation was confirmed using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and predominantly relative quantitative polymerase chain reaction (qPCR). RESULTS: In total, 5.9% (32/542) patients were positive for karyotypic abnormalities. Pathogenic/likely pathogenic CNVs were identified in 17.7% of them (96/542), variants of uncertain significance (VOUS) were detected in 4.8% (26/542) and likely benign CNVs in 9.2% of cases (50/542). We identified 6.6% (36/542) patients with known recurrent microdeletion (24 cases) and microduplication (12 cases) syndromes, as well as 4.8% (26/542) patients with non-recurrent rare microdeletions (21 cases) and microduplications (5 cases). In the group of patients with submicroscopic pathogenic/likely pathogenic CNVs (13.3%; 68/510) we identified 91.2% (62/68) patients with one CNV, 5.9% (4/68) patients with two likely independent CNVs and 2.9% (2/68) patients with two CNVs resulting from cryptic unbalanced translocations. Of all detected CNVs, 21% (31/147) had a de novo origin, 51% (75/147) were inherited and 28% (41/147) of unknown origin. In our cohort pathogenic/likely pathogenic microdeletions were more frequent than microduplications (69%; 51/74 vs. 31%; 23/74) ranging in size from 0.395 Mb to 10.676 Mb (microdeletions) and 0.544 Mb to 8.156 Mb (microduplications), but their sizes were not significantly different (P = 0.83). The pathogenic/likely pathogenic CNVs (median 2.663 Mb) were significantly larger than benign CNVs (median 0.394 Mb) (P < 0.00001) and likewise the pathogenic/likely pathogenic CNVs (median 2.663 Mb) were significantly larger in size than VOUS (median 0.469 Mb) (P < 0.00001). CONCLUSIONS: Our results confirm the benefit of array-CGH in the current clinical genetic diagnostics leading to identification of the genetic cause of ID/DD in affected children.

• Klíčová slova
• Array-CGH, CNV, Developmental delay, Intellectual disability, Microdeletion, Microduplication,
• MeSH
• dítě MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• mladiství MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů * MeSH
• srovnávací genomová hybridizace * MeSH
• variabilita počtu kopií segmentů DNA * MeSH
• vývojové poruchy u dětí genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10(-11)) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.

• MeSH
• faciální stigmatizace MeSH
• fenotyp MeSH
• genotyp MeSH
• guanosindifosfát metabolismus   MeSH
• guanosintrifosfát metabolismus   MeSH
• interakční proteinové domény a motivy genetika   MeSH
• konformace proteinů MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• missense mutace MeSH
• mitochondriální proteiny chemie   genetika   MeSH
• molekulární modely MeSH
• mutace * MeSH
• Ral proteiny vázající GTP chemie   genetika   MeSH
• Ras proteiny chemie   genetika   MeSH
• vývojové poruchy u dětí genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• guanosindifosfát MeSH
• guanosintrifosfát MeSH
• mitochondriální proteiny MeSH
• RAB40AL protein, human MeSH Prohlížeč
• Ral proteiny vázající GTP MeSH
• RALA protein, human MeSH Prohlížeč
• Ras proteiny MeSH

Background: A growing body of evidence attests to the disproportionate impact of COVID-19 on persons with intellectual and developmental disabilities (IDD) during the pandemic. This study asked caregivers about their perceptions of how COVID-19 impacted them and the people they support. Method: An online survey was conducted in 12 countries during August-September 2020 and sought information on demographics, support practices, information and training, experiences of COVID-19, social distancing, and wellbeing, as measured by the DASS12. This study reports on 3,754 family members, direct support professionals, and managers who participated in the survey. Results: Caregivers observed increases in depression/anxiety, stereotyped behaviours, aggression towards others and weight gain in the person(s) they supported. They also reported difficulties supporting the person(s) to access healthcare. Families reported reducing or ceasing employment and absorbed additional costs when supporting their family member. Direct support professionals experienced changes in staff shifts, staff absences, increased workload and hiring of casual staff. Caregivers' wellbeing revealed high levels of stress, depression, and less so anxiety. The strongest predictor of wellbeing among families was observation of changes in mood in the person(s) they supported, while for direct support professionals, the strongest predictors of wellbeing were reorganisation of staff shifts and increases in new direct support staff. Discussion: Findings support the contention of this population experiencing a disproportionate burden during the COVID-19 pandemic, reflecting historical inequities in access to healthcare and other human rights violations which are now protected under the United Nations Convention on the Rights of Persons with Disabilities.

• Klíčová slova
• COVID-19, Caregivers, Carers, Coronavirus, Health Disparity, Intellectual Disability, Intellectual and Developmental Disability, Pandemic,
• Publikační typ
• časopisecké články MeSH

Academic self-concept could significantly affect academic achievement and self-confidence in children with epilepsy. However, limited attention has been devoted to determining factors influencing academic self-concept of children with epilepsy. We aimed to analyze potentially significant variables (gender, frequency of seizures, duration of epilepsy, intellectual disability, learning disability and attention deficit hyperactivity disorder) in relation to academic self-concept in children with epilepsy and to additional domains of their quality of life. The study group consisted of 182 children and adolescents aged 9-14 years who completed the SPAS (Student's Perception of Ability Scale) questionnaire determining their academic self-concept and the modified Czech version of the CHEQOL-25 (Health-Related Quality of Life Measure for Children with Epilepsy) questionnaire evaluating their health-related quality of life. Using regression analysis, we identified learning disability as a key predictor for academic-self concept of children with epilepsy. While children with epilepsy and with no learning disability exhibited results comparable to children without epilepsy, participants with epilepsy and some learning disability scored significantly lower in almost all domains of academic self-concept. We moreover found that children with epilepsy and learning disability have significantly lower quality of life in intrapersonal and interpersonal domains. In contrast to children with epilepsy and with no learning disability, these participants have practically no correlation between their quality of life and academic self-concept. Our findings suggest that considerable attention should be paid to children having both epilepsy and learning disability. It should comprise services of specialized counselors and teaching assistants with an appropriate knowledge of epilepsy and ability to empathize with these children as well as educational interventions focused on their teachers and classmates.

• Klíčová slova
• Academic self-concept, Children, Epilepsy, Learning disability, Quality of life,
• MeSH
• dítě MeSH
• epilepsie komplikace   psychologie   MeSH
• hyperkinetická porucha komplikace   psychologie   MeSH
• kvalita života psychologie   MeSH
• lidé MeSH
• mentální retardace komplikace   psychologie   MeSH
• mladiství MeSH
• poruchy učení komplikace   psychologie   MeSH
• průzkumy a dotazníky MeSH
• sebepojetí * MeSH
• stupeň vzdělání MeSH
• úspěšnost MeSH
• výchova a vzdělávání MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.

• Klíčová slova
• FOXP1, genotype-phenotype correlation, intellectual disability, language impairment, oromotor dysfunction,
• MeSH
• fenotyp MeSH
• forkhead transkripční faktory chemie   genetika   metabolismus   MeSH
• genetická transkripce MeSH
• jazykové poruchy genetika   MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• missense mutace MeSH
• mutace MeSH
• neurovývojové poruchy genetika   MeSH
• obličej abnormality   MeSH
• poruchy autistického spektra genetika   MeSH
• poruchy motorických dovedností genetika   MeSH
• represorové proteiny chemie   genetika   metabolismus   MeSH
• stabilita proteinů MeSH
• syndrom MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• forkhead transkripční faktory MeSH
• FOXP1 protein, human MeSH Prohlížeč
• represorové proteiny MeSH

PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of "ribosomopathies."

• Klíčová slova
• ACTL6B, Autism, BAFopathies, Epileptic-dyskinetic encephalopathy, Ribosomopathies,
• MeSH
• dítě MeSH
• dominantní geny MeSH
• fenotyp MeSH
• geny recesivní MeSH
• jaderné proteiny * genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mentální retardace genetika   patologie   MeSH
• mladiství MeSH
• mozek patologie   MeSH
• mutace MeSH
• nemoci mozku * genetika   patologie   MeSH
• neurovývojové poruchy * genetika   MeSH
• předškolní dítě MeSH
• vývojové poruchy u dětí * genetika   patologie   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• jaderné proteiny * MeSH

PURPOSE: The purpose of this study was to expand the genetic architecture of neurodevelopmental disorders, and to characterize the clinical features of a novel cohort of affected individuals with variants in ZNF142, a C2H2 domain-containing transcription factor. METHODS: Four independent research centers used exome sequencing to elucidate the genetic basis of neurodevelopmental phenotypes in four unrelated families. Following bioinformatic filtering, query of control data sets, and secondary variant confirmation, we aggregated findings using an online data sharing platform. We performed in-depth clinical phenotyping in all affected individuals. RESULTS: We identified seven affected females in four pedigrees with likely pathogenic variants in ZNF142 that segregate with recessive disease. Affected cases in three families harbor either nonsense or frameshifting likely pathogenic variants predicted to undergo nonsense mediated decay. One additional trio bears ultrarare missense variants in conserved regions of ZNF142 that are predicted to be damaging to protein function. We performed clinical comparisons across our cohort and noted consistent presence of intellectual disability and speech impairment, with variable manifestation of seizures, tremor, and dystonia. CONCLUSION: Our aggregate data support a role for ZNF142 in nervous system development and add to the emergent list of zinc finger proteins that contribute to neurocognitive disorders.

• Klíčová slova
• ataxia, childhood apraxia of speech, developmental delay, dolichocephaly, homozygosity mapping,
• MeSH
• dítě MeSH
• dospělí MeSH
• dystonie genetika   MeSH
• fenotyp MeSH
• kohortové studie MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• missense mutace MeSH
• mladiství MeSH
• mutace MeSH
• neurovývojové poruchy genetika   MeSH
• poruchy řeči genetika   MeSH
• rodina MeSH
• rodokmen MeSH
• sekvenování exomu MeSH
• trans-aktivátory genetika   metabolismus   MeSH
• výpočetní biologie metody   MeSH
• vývojové poruchy u dětí genetika   MeSH
• záchvaty genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• trans-aktivátory MeSH
• ZNF143 protein, human MeSH Prohlížeč