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Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function.
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This study investigated the neurodevelopmental impact of pathogenic adenomatous polyposis coli (APC) gene variants in patients with familial adenomatous polyposis (FAP), a cancer predisposition syndrome. We hypothesized that certain pathogenic APC variants result in behavioral-cognitive challenges. We compared 66 FAP patients (cases) and 34 unaffected siblings (controls) to explore associations between APC variants and behavioral and cognitive challenges. Our findings indicate that FAP patients exhibited higher Social Responsiveness Scale (SRS) scores, suggesting a greater prevalence of autistic traits when compared to unaffected siblings (mean 53.8 vs. 47.4, Wilcoxon p = 0.018). The distribution of SRS scores in cases suggested a bimodal pattern, potentially linked to the location of the APC variant, with scores increasing from the 5' to 3' end of the gene (Pearson's r = 0.33, p = 0.022). While we observed a trend toward lower educational attainment in cases, this difference was not statistically significant. This study is the first to explore the connection between APC variant location and neurodevelopmental traits in FAP, expanding our understanding of the genotype-phenotype correlation. Our results emphasize the importance of clinical assessment for autistic traits in FAP patients, shedding light on the potential role of APC gene variants in these behavioral and cognitive challenges.
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BACKGROUND: A sizeable proportion of pathogenic genetic variants identified in young children tested for congenital differences are associated with neurodevelopmental psychiatric disorders (NPD). In this growing group, a genetic diagnosis often precedes the emergence of diagnosable developmental concerns. Here, we describe DAGSY (Developmental Assessment of Genetically Susceptible Youth), a novel interdisciplinary 'genetic-diagnosis-first' clinic integrating psychiatric, psychological and genetic expertise, and report our first observations and feedback from families and referring clinicians. METHODS: We retrieved data on referral sources and indications, genetic and NPD diagnoses and recommendations for children seen at DAGSY between 2018 and 2022. Through a survey, we obtained feedback from twenty families and eleven referring clinicians. RESULTS: 159 children (mean age 10.2 years, 57.2% males) completed an interdisciplinary (psychiatry, psychology, genetic counselling) DAGSY assessment during this period. Of these, 69.8% had a pathogenic microdeletion or microduplication, 21.5% a sequence-level variant, 4.4% a chromosomal disorder, and 4.4% a variant of unknown significance with emerging evidence of pathogenicity. One in four children did not have a prior NPD diagnosis, and referral to DAGSY was motivated by their genetic vulnerability alone. Following assessment, 76.7% received at least one new NPD diagnosis, most frequently intellectual disability (24.5%), anxiety (20.7%), autism spectrum (18.9%) and specific learning (16.4%) disorder. Both families and clinicians responding to our survey expressed satisfaction, but also highlighted some areas for potential improvement. CONCLUSIONS: DAGSY addresses an unmet clinical need for children identified with genetic variants that confer increased vulnerability for NPD and provides a crucial platform for research in this area. DAGSY can serve as a model for interdisciplinary clinics integrating child psychiatry, psychology and genetics, addressing both clinical and research needs for this emerging population.
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Transtornos Mentais , Transtornos do Neurodesenvolvimento , Humanos , Criança , Transtornos do Neurodesenvolvimento/genética , Feminino , Masculino , Transtornos Mentais/genética , Predisposição Genética para Doença , AdolescenteRESUMO
Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the 6 domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and "behavioural issues", or about the type/nature of feeding problems. Follow-up reports (n = 95) rarely contributed this additional phenotype data. In summary, phenotype information relevant to clinical management, genetic counselling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. The PHELIX (PHEnotype LIsting fiX) reporting guideline checklists were developed to improve phenotype reporting in the genomic era.
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A 7-year-old girl presented with persistent anxiety symptoms for several years following gene therapy for an ultrarare neurometabolic disorder (aromatic L-amino acid decarboxylase [AADC] deficiency). AADC is the final enzyme in the monoamine synthesis pathway (Figure 1).1 Its absence results in a severe combined deficiency in serotonin, dopamine, epinephrine, and norepinephrine, causing significant developmental delays, hypotonia, and dystonia. The incidence of AADC deficiency is estimated at â¼1 in 500,000,2 and â¼200 cases have been described.1 Recently available disease-modifying gene therapy for this condition dramatically improves motor symptoms, and received regulatory approval in some regions in 2022.2 There are no data to guide psychiatric care post gene therapy for AADC or other neurologic disorders to date.3.
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Descarboxilases de Aminoácido-L-Aromático , Terapia Genética , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Feminino , Criança , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Descarboxilases de Aminoácido-L-Aromático/deficiência , Descarboxilases de Aminoácido-L-Aromático/genética , Terapia Genética/métodos , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapiaRESUMO
Many rare genetic variants are associated with the risk of atypical neurodevelopmental trajectories. In this study, we report a patient with developmental delay, autistic traits and multiple congenital anomalies, including congenital heart anomalies and orofacial cleft, with a 0.832 Mb de novo deletion of the 16p13.13 region classified as a variant of uncertain significance. Comparison of similar sized deletions and duplications overlapping the same genes in the DECIPHER database, revealed seven reports of copy number variants (CNVs), four duplications and three deletions. A neurodevelopmental phenotype including learning disability and intellectual disability was noted in some of the DECIPHER entries where phenotype was provided. Although the association between a deletion in this region and an atypical neurodevelopmental trajectory remains to be elucidated, the overlapping CNVs with neurodevelopmental phenotypes suggests possible candidate genes within the 16p13.13 region.
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Anormalidades Múltiplas , Fenda Labial , Fissura Palatina , Deficiência Intelectual , Humanos , Deficiência Intelectual/genética , Anormalidades Múltiplas/genética , Variações do Número de Cópias de DNA/genéticaRESUMO
22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.
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Síndrome de DiGeorge , Transtornos Psicóticos , Feminino , Humanos , Adolescente , Masculino , Síndrome de DiGeorge/diagnóstico por imagem , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Transtornos Psicóticos/complicações , Substância Cinzenta/diagnóstico por imagemRESUMO
AIM: A first episode of psychosis (FEP) is a stressful, often life-changing experience. Scarce information is available about personal preferences regarding their care needs during and after a FEP. Whereas a more thorough understanding of these preferences is essential to aid shared decision-making during treatment and improve treatment satisfaction. METHODS: Face-to-face interviews with participants in remission of a FEP were set up, addressing personal preferences and needs for care during and after a FEP. The interviews were conducted by a female and a male researcher, the latter being an expert with lived experience. RESULTS: Twenty individuals in remission of a FEP were interviewed, of which 16 had been hospitalized. The distinguished themes based on personal preferences were tranquillity, peace and quietness, information, being understood, support from significant others, and practical guidance in rebuilding one's life. Our findings revealed that the need for information and the need to be heard were often not sufficiently met. For 16/20 participants, the tranquillity of inpatient treatment of the FEP was predominantly perceived as a welcome safe haven. The presence and support of family and close friends were mentioned as an important factor in the process of achieving remission. CONCLUSIONS: The current exploratory study showed that patients were able to indicate their personal needs. Important findings are the need for information and the need to be heard. Interestingly, hospitalization was mostly seen as an opportunity to achieve tranquillity. More lived experience expertise is needed to elucidate the needs of individuals in the early phase of a FEP to aid people who are recovering from their first psychosis in rebuilding their lives again.
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PURPOSE: Developmental language disorder (DLD) is characterized by persistent and unexplained difficulties in language development. Accumulating evidence shows that children with DLD also present with deficits in other cognitive domains, such as executive functioning (EF). There is an ongoing debate on whether exclusively verbal EF abilities are impaired in children with DLD or whether nonverbal EF is also impaired, and whether these EF impairments are related to their language difficulties. The aims of this study were to (a) compare nonverbal performance of preschoolers with DLD and typically developing (TD) peers, (b) examine how nonverbal EF and language abilities are related, and (c) investigate whether a diagnosis of DLD moderates the relationship between EF and language abilities. METHOD: A total of 143 children (nDLD = 65, nTD = 78) participated. All children were between 3 and 6.5 years old and were monolingual Dutch. We assessed nonverbal EF with a visual selective attention task, a visuospatial short-term and working memory task, and a task gauging broad EF abilities. Vocabulary and morphosyntax were each measured with two standardized language tests. We created latent variables for EF, vocabulary, and morphosyntax. RESULTS: Analyses showed that children with DLD were outperformed by their TD peers on all nonverbal EF tasks. Nonverbal EF abilities were related to morphosyntactic abilities in both groups, whereas a relationship between vocabulary and EF skills was found in the TD group only. These relationships were not significantly moderated by a diagnosis of DLD. CONCLUSIONS: We found evidence for nonverbal EF impairments in preschool children with DLD. Moreover, nonverbal EF and morphosyntactic abilities were significantly related in these children. These findings may have implications for intervention and support the improvement of prognostic accuracy. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24121287.
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Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.
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Background and Aim: Children with Developmental Language Disorder (DLD) are at an increased risk to develop behaviors associated with Autism Spectrum Disorder (ASD). The relationship between early language difficulties and the occurrence of ASD-related behaviors in DLD is poorly understood. One factor that may hinder progress in understanding this relationship is the etiological heterogeneity of DLD. We therefore study this relationship in an etiologically homogeneous group of children, who share phenotypic characteristics with children with DLD: children with the 22q11.2 Deletion Syndrome (22q11DS). We compare children with 22q11DS, to children with DLD and age-matched typically developing children (TD). Method: 44 children with 22q11DS, 65 children with DLD and 81 TD children, between 3.0-6.5 years old, participated in a longitudinal cohort study that included a baseline measure and a follow-up measure with a 1-year interval. A parental questionnaire (SRS-2) was used to measure the incidence of behaviors in two key behavioral domains associated with ASD: Social Communication and Interaction and Restricted Repetitive Behaviors and Interests. At baseline, we assessed children's expressive and receptive language abilities as well as their intellectual functioning with standardized tests. We compared the distribution of ASD-related behaviors between the three groups. We used regression analyses to investigate whether language abilities at baseline predict ASD-related behavior at follow-up, accounting for ASD-related behavior at baseline, demographic variables and intellectual functioning. Results: Both the children with 22q11DS and the children with DLD displayed significantly more ASD-related behaviors than the TD children. Over 30% of children in both clinical groups had scores exceeding the subclinical threshold for ASD in both behavioral domains. Both in 22q11DS and DLD, baseline receptive language scores were negatively correlated with ASD-related behaviors 1 year later, when controlling for baseline SRS-scores. However, this association was statistically significant only in children with 22q11DS, even when controlled for IQ-scores, and it was significantly stronger as than in the TD group. The strength of the association did not differ significantly between 22q11DS and DLD. Conclusion: Both children with 22q11DS and children with DLD present with elevated rates of ASD-related behaviors at a preschool-age. Only in children with 22q11DS we observed that weaker receptive language skills were related to increased behavioral problems in the domain of social communication and interaction one year later. Implications: Our findings indicate that relations between early language impairment and other behavioral phenotypes may be more feasible to detect in a subgroup of children with a homogeneous etiology, than in a group of children with a heterogeneous etiology (such as children with DLD). Our results in 22q11DS reveal that receptive language is especially important in predicting the occurrence of ASD-related behaviors. Future research is needed to determine to what extent receptive language predicts the occurrence of ASD-related behaviors in children with DLD, especially among those children with DLD with the weakest receptive language. Clinically, screening for ASD-related behaviors in children with developmental language difficulties is recommended from a young age, especially among children with receptive language difficulties.
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We assessed the relationship of gene copy number variation (CNV) in mental health/neurodevelopmental traits and diagnoses, physical health and cognition in a community sample of 7100 unrelated children and youth of European or East Asian ancestry (Spit for Science). Clinically significant or susceptibility CNVs were present in 3.9% of participants and were associated with elevated scores on a continuous measure of attention-deficit/hyperactivity disorder (ADHD) traits (P = 5.0 × 10-3), longer response inhibition (a cognitive deficit found in several mental health and neurodevelopmental disorders; P = 1.0 × 10-2) and increased prevalence of mental health diagnoses (P = 1.9 × 10-6, odds ratio: 3.09), specifically ADHD, autism spectrum disorder anxiety and learning problems/learning disorder (P's < 0.01). There was an increased burden of rare deletions in gene-sets related to brain function or expression in brain associated with more ADHD traits. With the current mental health crisis, our data established a baseline for delineating genetic contributors in pediatric-onset conditions.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Adolescente , Humanos , Criança , Saúde Mental , Variações do Número de Cópias de DNA/genética , Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Dosagem de GenesRESUMO
BACKGROUND: Executive functioning (EF) is an umbrella term for various cognitive functions that play a role in monitoring and planning to effectuate goal-directed behavior. The 22q11.2 deletion syndrome (22q11DS), the most common microdeletion syndrome, is associated with a multitude of both somatic and cognitive symptoms, including EF impairments in school-age and adolescence. However, results vary across different EF domains and studies with preschool children are scarce. As EF is critically associated with later psychopathology and adaptive functioning, our first aim was to study EF in preschool children with 22q11DS. Our second aim was to explore the effect of a congenital heart defects (CHD) on EF abilities, as CHD are common in 22q11DS and have been implicated in EF impairment in individuals with CHD without a syndromic origin. METHODS: All children with 22q11DS (n = 44) and typically developing (TD) children (n = 81) were 3.0 to 6.5 years old and participated in a larger prospective study. We administered tasks measuring visual selective attention, visual working memory, and a task gauging broad EF abilities. The presence of CHD was determined by a pediatric cardiologist based on medical records. RESULTS: Analyses showed that children with 22q11DS were outperformed by TD peers on the selective attention task and the working memory task. As many children were unable to complete the broad EF task, we did not run statistical analyses, but provide a qualitative description of the results. There were no differences in EF abilities between children with 22q11DS with and without CHDs. CONCLUSION: To our knowledge, this is the first study measuring EF in a relatively large sample of young children with 22q11DS. Our results show that EF impairments are already present in early childhood in children with 22q11DS. In line with previous studies with older children with 22q11DS, CHDs do not appear to have an effect on EF performance. These findings might have important implications for early intervention and support the improvement of prognostic accuracy.
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Síndrome de DiGeorge , Adolescente , Humanos , Pré-Escolar , Criança , Síndrome de DiGeorge/complicações , Estudos Prospectivos , Função Executiva , Cognição , AtençãoRESUMO
Diagnosis of pathogenic genetic variants associated with neurodevelopmental and psychiatric disorders (NPDs) is increasingly made early in life. This narrative review focuses on the need for, and provision of, psychological supports following genetic diagnosis. We conducted a literature search of publications on how caregivers are informed about the NPD vulnerability associated with genetic variants, challenges and unmet needs when receiving this information, and whether psychological supports are provided. Given its early recognition, the 22q11.2 deletion has been studied thoroughly for two decades, providing generalizable insights. This literature indicates the complex caregivers' needs related to learning about potential NPD vulnerabilities associated with a genetic variant, include how to communicate the diagnosis, how to identify early signs of NPDs, how to deal with stigma and a lack of medical expertise outside of specialized genetics clinics. With one exception, no publications describe psychotherapeutic support provided to parents. In the absence of support, caregivers struggle with several unmet needs regarding potential longer-term NPD implications of a genetic diagnosis. The field needs to go beyond explaining genetic diagnoses and associated vulnerabilities, and develop approaches to support caregivers with communicating and managing NPD implications across the child's lifespan.
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Cuidadores , Transtornos Mentais , Humanos , Criança , Pré-Escolar , Cuidadores/psicologia , Pais , Transtornos Mentais/diagnóstico , Transtornos Mentais/genéticaRESUMO
22q11.2 deletion is one of the strongest known genetic risk factors for schizophrenia. Recent whole-genome sequencing of schizophrenia cases and controls with this deletion provided an unprecedented opportunity to identify risk modifying genetic variants and investigate their contribution to the pathogenesis of schizophrenia in 22q11.2 deletion syndrome. Here, we apply a novel analytic framework that integrates gene network and phenotype data to investigate the aggregate effects of rare coding variants and identified modifier genes in this etiologically homogenous cohort (223 schizophrenia cases and 233 controls of European descent). Our analyses revealed significant additive genetic components of rare nonsynonymous variants in 110 modifier genes (adjusted P = 9.4E-04) that overall accounted for 4.6% of the variance in schizophrenia status in this cohort, of which 4.0% was independent of the common polygenic risk for schizophrenia. The modifier genes affected by rare coding variants were enriched with genes involved in synaptic function and developmental disorders. Spatiotemporal transcriptomic analyses identified an enrichment of coexpression between modifier and 22q11.2 genes in cortical brain regions from late infancy to young adulthood. Corresponding gene coexpression modules are enriched with brain-specific protein-protein interactions of SLC25A1, COMT, and PI4KA in the 22q11.2 deletion region. Overall, our study highlights the contribution of rare coding variants to the SCZ risk. They not only complement common variants in disease genetics but also pinpoint brain regions and developmental stages critical to the etiology of syndromic schizophrenia.
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Síndrome de DiGeorge , Esquizofrenia , Humanos , Adulto Jovem , Adulto , Esquizofrenia/genética , Síndrome de DiGeorge/genética , Encéfalo , Perfilação da Expressão Gênica , Sequenciamento Completo do GenomaRESUMO
This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.
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Síndrome de DiGeorge , Adolescente , Humanos , Criança , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/terapia , Aconselhamento Genético , Inquéritos e QuestionáriosRESUMO
PURPOSE: Young children with 22q11.2 deletion syndrome (22q11DS) often have impaired language development and poor speech intelligibility. Here, we report a comprehensive overview of standardized language assessment in a relatively large sample of preschool-aged children with 22q11DS. We furthermore explored whether speech ability explained variability in language skills. METHOD: Forty-four monolingual Dutch preschoolers (3-6 years) with a confirmed genetic 22q11DS diagnosis participated in this prospective cohort study. Standardized tests (Clinical Evaluation of Language Fundamentals Preschool-2-NL and Peabody Picture Vocabulary Test-III-NL) were administered. Speech intelligibility was rated by two expert speech and language therapists using a standardized procedure. RESULTS: Most children had impaired language skills across all tested domains. The composite score for expressive language was significantly lower than that for receptive language, but the two were strongly correlated. Only small differences between the mean scores on the various subtests were observed, with the lowest scores for expressive morphosyntactic skills. Language scores showed a moderate positive relation with speech intelligibility, but language abilities varied greatly among the children with intelligible speech. CONCLUSIONS: We show that the majority of preschool children with 22q11DS have a broad range of language problems. Other than the relatively larger impairment in expressive than in receptive language skills, our results do not show a clearly delineated language profile. As many of the children with intelligible speech still had below-average language scores, we highlight that language problems require a broad assessment and care in all young children with 22q11DS. Future research using spontaneous language and detailed speech analysis is recommended, to provide more in-depth understanding of children's language profile and the relationship between speech and language in 22q11DS.
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Transtornos da Comunicação , Síndrome de DiGeorge , Humanos , Pré-Escolar , Inteligibilidade da Fala , Estudos Prospectivos , Distúrbios da Fala/diagnósticoRESUMO
Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant? In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype-phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population. We conclude with research priorities for the field, which may pave the way for novel therapeutics.
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Transtorno do Espectro Autista , Transtorno Autístico , Síndrome de DiGeorge , Esquizofrenia , Animais , Humanos , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/patologia , Esquizofrenia/genética , Esquizofrenia/complicações , Transtorno Autístico/genética , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/complicações , FenótipoRESUMO
Bipolar disorder (BD) is a potentially chronic mental disorder marked by recurrent depressive and manic episodes, circadian rhythm disruption, and changes in energetic metabolism. "Metabolic jet lag" refers to a state of shift in circadian patterns of energy homeostasis, affecting neuroendocrine, immune, and adipose tissue function, expressed through behavioral changes such as irregularities in sleep and appetite. Risk factors include genetic variation, mitochondrial dysfunction, lifestyle factors, poor gut microbiome health and abnormalities in hunger, satiety, and hedonistic function. Evidence suggests metabolic jet lag is a core component of BD pathophysiology, as individuals with BD frequently exhibit irregular eating rhythms and circadian desynchronization of their energetic metabolism, which is associated with unfavorable clinical outcomes. Although current diagnostic criteria lack any assessment of eating rhythms, technological advancements including mobile phone applications and ecological momentary assessment allow for the reliable tracking of biological rhythms. Overall, methodological refinement of metabolic jet lag assessment will increase knowledge in this field and stimulate the development of interventions targeting metabolic rhythms, such as time-restricted eating.