Background
Recent large‐scale initiatives have led to systematically collected phenotypic data for several rare genetic conditions implicated in autism spectrum disorder (ASD). The onset of ...developmentally expected skills (e.g. walking, talking) serve as readily quantifiable aspects of the behavioral phenotype. This study's aims were: (a) describe the distribution of ages of attainment of gross motor and expressive language milestones in several rare genetic conditions, and (b) characterize the likelihood of delays in these conditions compared with idiopathic ASD.
Methods
Participants aged 3 years and older were drawn from two Simons Foundation Autism Research Initiative registries that employed consistent phenotyping protocols. Inclusion criteria were a confirmed genetic diagnosis of one of 16 genetic conditions (Simons Searchlight) or absence of known pathogenic genetic findings in individuals with ASD (SPARK). Parent‐reported age of acquisition of three gross motor and two expressive language milestones was described and categorized as on‐time or delayed, relative to normative expectations.
Results
Developmental milestone profiles of probands with genetic conditions were marked by extensive delays (including nonattainment), with highest severity in single gene conditions and more delays than idiopathic ASD in motor skills. Compared with idiopathic ASD, the median odds of delay among the genetic groups were higher by 8.3 times (IQR 5.8–16.3) for sitting, 12.4 times (IQR 5.3–19.5) for crawling, 26.8 times (IQR 7.7–41.1) for walking, 2.7 times (IQR 1.7–5.5) for single words, and 5.7 times (IQR 2.7–18.3) for combined words.
Conclusions
Delays in developmental milestones, particularly in gross motor skills, are frequent and may be among the earliest indicators of differentially affected developmental processes in specific genetically defined conditions associated with ASD, as compared with those with clinical diagnoses of idiopathic ASD. The possibility of different developmental pathways leading to ASD‐associated phenotypes should be considered when deciding how to employ specific genetic conditions as models for ASD.
Expressive language impairment is one of the most frequently associated clinical features of 16p11.2 copy number variations (CNV). However, our understanding of the language profiles of individuals ...with 16p11.2 CNVs is still limited. This study builds upon previous work in the Simons Variation in Individuals Project (VIP, now known as Simons Searchlight), to characterize language abilities in 16p11.2 deletion and duplication carriers using comprehensive assessments. Participants included 110 clinically ascertained children and family members (i.e., siblings and cousins) with 16p11.2 BP4‐BP5 deletion and 58 with 16p11.2 BP4‐BP5 duplication between the ages of 2–23 years, most of whom were verbal. Regression analyses were performed to quantify variation in language abilities in the presence of the 16p11.2 deletion and duplication, both with and without autism spectrum disorder (ASD) and cognitive deficit. Difficulties in pragmatic skills were equally prevalent in verbal individuals in both deletion and duplication groups. NVIQ had moderate quantifiable effects on language scores in syntax and semantics/pragmatics (a decrease of less than 1 SD) for both groups. Overall, language impairments persisted even after controlling for ASD diagnosis and cognitive deficit. Language impairment is one of the core clinical features of individuals with 16p11.2 CNVs even in the absence of ASD and cognitive deficit. Results highlight the need for more comprehensive and rigorous assessment of language impairments to maximize outcomes in carriers of 16p11.2 CNVs.
DYRK1A haploinsufficiency syndrome is a well‐established neurodevelopmental disorder, but detailed information on the range of cognitive and behavioral issues associated with the condition is ...limited. We studied 24 participants with likely pathogenic or pathogenic variants in DYRK1A through the Simons Searchlight study and systematically assessed their medical history and development using standardized instruments: Vineland Adaptive Behavior Scale II (VABS‐II) and Child Behavior Checklists/1.5‐5 and 6‐18 (CBCL/1.5‐5, CBCL/6‐18). All of the individuals in the cohort had neurological manifestations including intellectual disability or developmental delay, microcephaly, autism spectrum disorder, and/or seizures. The severity of the neurodevelopmental disorder was variable with a few children scoring in the moderately low range on the adaptive behavior composite score on the VABS‐II. This study confirms the association of DYRK1A haploinsufficiency with neurodevelopmental disabilities, microcephaly, autism spectrum disorder, and epilepsy and quantifies the range of adaptive behaviors.
AbstractBackgroundDeletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond ...language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported. MethodsThis study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects. ResultsIQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs. ConclusionsThe simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances.
This study focused on the development and initial psychometric evaluation of a set of online, webcam-collected, and artificial intelligence-derived patient performance measures for neurodevelopmental ...genetic syndromes (NDGS). Initial testing and qualitative input was used to develop four stimulus paradigms capturing social and cognitive processes, including social attention, receptive vocabulary, processing speed, and single-word reading. The paradigms were administered to a sample of 375 participants, including 163 with NDGS, 56 with idiopathic neurodevelopmental disability (NDD), and 156 neurotypical controls. Twelve measures were created from the four stimulus paradigms. Valid completion rates varied from 87 to 100% across measures, with lower but adequate completion rates in participants with intellectual disability. Adequate to excellent internal consistency reliability (α = 0.67 to 0.95) was observed across measures. Test-retest reproducibility at 1-month follow-up and stability at 4-month follow-up was fair to good (r = 0.40-0.73) for 8 of the 12 measures. All gaze-based measures showed evidence of convergent and discriminant validity with parent-report measures of other cognitive and behavioral constructs. Comparisons across NDGS groups revealed distinct patterns of social and cognitive functioning, including people with PTEN mutations showing a less impaired overall pattern and people with SYNGAP1 mutations showing more attentional, processing speed, and social processing difficulties relative to people with NFIX mutations. Webcam-collected performance measures appear to be a reliable and potentially useful method for objective characterization and monitoring of social and cognitive processes in NDGS and idiopathic NDD. Additional validation work, including more detailed convergent and discriminant validity analyses and examination of sensitivity to change, is needed to replicate and extend these observations.
Aim
To determine the views of individuals with cerebral palsy (CP) and their caregivers (CP community members) about carrying a CP diagnosis, an etiological diagnosis, or both diagnoses together.
...Method
We surveyed CP community members across two registries querying their views on carrying a CP diagnosis, one type of etiological diagnosis (specifically, a genetic diagnosis), or both. Open‐ended responses were analyzed using a conventional content analysis approach.
Results
Of 197 respondents (108 adults with CP and 89 caregivers), most (75%) valued knowing the cause of their CP. Of those with a diagnostic preference, most preferred carrying both CP and etiological diagnoses together (68%). When compared with carrying an etiological diagnosis alone, significantly more respondents felt a CP diagnosis helped anticipate symptom evolution (84% vs 54%), explain symptoms to others (86% vs 48%), access services (86% vs 48%), and join support communities (78% vs 50%) (p < 0.01, χ2 test).
Interpretation
Most CP community members surveyed want to know the cause of their CP and would prefer carrying both CP and etiological diagnoses together. Clinical practice should evolve to meet these community needs.
Resumen
Objetivo
Determinar las opiniones de las personas con parálisis cerebral (PC) y sus cuidadores (miembros de la comunidad de PC) acerca de tener un diagnóstico de PC, un diagnóstico etiológico o ambos diagnósticos juntos.
Método
Encuestamos a miembros de la comunidad de PC en dos registros de PC para consultar sus opiniones sobre tener un diagnóstico de PC, un tipo de diagnóstico etiológico (específicamente, un diagnóstico genético) o ambos. Las respuestas abiertas se analizaron utilizando un enfoque de análisis de contenido convencional.
Resultados
De 197 encuestados (108 adultos con PC y 89 cuidadores), la mayoría (75%) valoró conocer la causa de su PC. De aquellos con una preferencia diagnóstica, la mayoría prefirió tener diagnósticos etiológicos y de PC juntos (68%). En comparación con tener un diagnóstico etiológico solo, significativamente más encuestados sintieron que un diagnóstico de PC ayudó a anticipar la evolución de los síntomas (84% frente a 54%), explicar los síntomas a otros (86% frente a 48%), acceder a los servicios (86% frente a 48%), y unirse a comunidades de apoyo (78% frente a 50%) (p<0,01, prueba de χ2).
Interpretación
La mayoría de los miembros encuestados de la comunidad de PC quieren saber la causa de su PC y preferirían tener juntos tanto el diagnóstico de PC como el diagnóstico etiológico. La práctica clínica debe evolucionar para satisfacer estas necesidades de la comunidad.
Resumo
Objetivo
Determinar a opinião de pessoas com paralisia cerebral (PC) e seus cuidadores (membros com PC da comunidade) sobre a realização de um diagnóstico de PC, um diagnóstico etiológico ou ambos os diagnósticos juntos.
Método
Pesquisamos membros da comunidade com PC em dois registros, questionando suas opiniões sobre o diagnóstico de PC, um tipo de diagnóstico etiológico (especificamente, um diagnóstico genético) ou ambos. As respostas abertas foram analisadas usando uma abordagem convencional de análise de conteúdo
Resultados
Dos 197 entrevistados (108 adultos com PC e 89 cuidadores), a maioria (75%) valorizou conhecer a causa de sua PC. Daqueles com preferência diagnóstica, a maioria preferiu conhecer tanto o diagnóstico de PC quanto o diagnóstico etiológico (68%). Quando comparado com o diagnóstico etiológico isolado, significativamente mais entrevistados sentiram que o diagnóstico de PC ajudou a antecipar a evolução dos sintomas (84% vs 54%), explicar os sintomas a outras pessoas (86% vs 48%), acessar serviços (86% vs 48%), e participar de comunidades de apoio (78% vs 50%) (p<0,01, teste χ2).
Interpretação
A maioria dos membros com PC da comunidade pesquisados deseja saber a causa de sua PC e preferiria realizar o diagnóstico de PC e etiológico juntos. A prática clínica deve evoluir para atender a essas necessidades da comunidade.
This original article is commented on by Smithers‐Sheedy and Henry on pages 675–676 of this issue.
Assessing cognitive development is critical in clinical research of autism spectrum disorder (ASD). However, collecting cognitive data from clinically administered assessments can add a significant ...burden to clinical research in ASD due to the substantial cost and time required, and it is often prohibitive in large‐scale studies. There is a need for more efficient, but reliable, methods to estimate cognitive functioning for researchers, clinicians, and families. To examine the degree to which caregiver estimates of cognitive level agree with actual measured intelligence/developmental scores and understand factors that may impact that agreement, 1,555 autistic individuals (81.74% male; age 18 months–18 years) were selected from a large cohort (Simons Foundation Powering Autism Research for Knowledge, SPARK). Results suggest that querying parents about recent testing results and developmental diagnoses can provide valid and useful information on cognitive ability. The agreement of parental estimates varied with age, measured cognitive ability, autistic traits, and adaptive skills. In the context of large‐scale research efforts, parent‐reported cognitive impairment may be a good proxy for categorical IQ range for survey‐based studies when specific IQ scores are not available, circumventing the logistical and financial obstacles of obtaining neuropsychological or neurodevelopmental testing.
Lay Summary
We found that simply asking parents about their child's recent testing results, delays, and developmental diagnoses can provide valid and useful estimation about the child's cognitive ability. The agreement of the parent's estimate with actual test results depends on the child's age, tested cognitive ability, autistic traits, and their everyday skills. Parent‐reported cognitive ability may be a good substitute for direct testing of cognitive ability, which can take long periods of time and be expensive.
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