Results from RATSS
On this page you will find abstracts and links to selected papers from RATSS, as well as links to related projects.
The Roots of Autism and ADHD Twin Study in Sweden (RATSS)
Neurodevelopmental disorders affect a substantial minority of the general population. Their origins are still largely unknown, but a complex interplay of genetic and environmental factors causing disturbances of the central nervous system's maturation and a variety of higher cognitive skills is presumed. Only limited research of rather small sample size and narrow scope has been conducted in neurodevelopmental disorders using a twin-differences design. The Roots of Autism and ADHD Twin Study in Sweden (RATSS) is an ongoing project targeting monozygotic twins discordant for categorical or dimensional autistic and inattentive/hyperactive-impulsive phenotypes as well as other neurodevelopmental disorders, and typically developing twin controls. Included pairs are 9 years of age or older, and comprehensively assessed for psychopathology, medical history, neuropsychology, and dysmorphology, as well as structural, functional, and molecular brain imaging. Specimens are collected for induced pluripotent (iPS) and neuroepithelial stem cells, genetic, gut bacteria, protein-/monoamine, and electron microscopy analyses. RATSS's objective is to generate a launch pad for novel surveys to understand the complexity of genotype-environment-phenotype interactions in autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD). By October 2013, RATSS had collected data from 55 twin pairs, among them 10 monozygotic pairs discordant for autism spectrum disorder, seven for ADHD, and four for other neurodevelopmental disorders. This article describes the design, recruitment, data collection, measures, collected pairs’ characteristics, as well as ongoing and planned analyses in RATSS. Potential gains of the study comprise the identification of environmentally mediated biomarkers, the emergence of candidates for drug development, translational modeling, and new leads for prevention of incapacitating outcomes.
Fetal and postnatal metal dysregulation in autism
Genetic and environmental factors contribute to the etiologies of autism spectrum disorder (ASD), but evidence of specific environmental exposures and susceptibility windows is limited. Here we study monozygotic and dizygotic twins discordant for ASD to test whether fetal and postnatal metal dysregulation increases ASD risk. Using validated tooth-matrix biomarkers, we estimate pre- and post-natal exposure profiles of essential and toxic elements. Significant divergences are apparent in metal uptake between ASD cases and their control siblings, but only during discrete developmental periods. Cases have reduced uptake of essential elements manganese and zinc, and higher uptake of the neurotoxin lead. Manganese and lead are also correlated with ASD severity and autistic traits. Our study suggests that metal toxicant uptake and essential element deficiency during specific developmental windows increases ASD risk and severity, supporting the hypothesis of systemic elemental dysregulation in ASD. Independent replication in population-based studies is needed to extend these findings.
Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder
Metals are critical to neurodevelopment, and dysregulation in early life has been documented in autism spectrum disorder (ASD). However, underlying mechanisms and biochemical assays to distinguish ASD cases from controls remain elusive. In a nationwide study of twins in Sweden, we tested whether zinc-copper cycles, which regulate metal metabolism, are disrupted in ASD. Using novel tooth-matrix biomarkers that provide direct measures of fetal elemental uptake, we developed a predictive model to distinguish participants who would be diagnosed with ASD in childhood from those who did not develop the disorder. We replicated our findings in three independent studies in the United States and the UK. We show that three quantifiable characteristics of fetal and postnatal zinc-copper rhythmicity are altered in ASD: the average duration of zinc-copper cycles, regularity with which the cycles recur, and the number of complex features within a cycle. In all independent study sets and in the pooled analysis, zinc-copper rhythmicity was disrupted in ASD cases. In contrast to controls, in ASD cases, the cycle duration was shorter (F = 52.25, P < 0.001), regularity was reduced (F = 47.99, P < 0.001), and complexity diminished (F = 57.30, P < 0.001). With two distinct classification models that used metal rhythmicity data, we achieved 90% accuracy in classifying cases and controls, with sensitivity to ASD diagnosis ranging from 85 to 100% and specificity ranging from 90 to 100%. These findings suggest that altered zinc-copper rhythmicity precedes the emergence of ASD, and quantitative biochemical measures of metal rhythmicity distinguish ASD cases from controls.
Dynamical properties of elemental metabolism distinguish attention deficit hyperactivity disorder from autism spectrum disorder
Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions of overlapping etiologies and phenotypes. For ASD, we recently reported altered elemental metabolic patterns in the form of short and irregular zinc and copper cycles. Here, we extend the application of these biomarkers of prenatal and early postnatal elemental metabolism to distinguish between individuals diagnosed with ADHD and/or ASD and neurotypical controls. We recruited twins discordant for ADHD, ASD and other neurodevelopmental diagnoses from national twin studies in Sweden (N=74) diagnosed according to DSM-5 clinical consensus and standardized psychiatric instruments. Detailed temporal profiles of exposure to 10 metals over the prenatal and early childhood periods were measured using tooth biomarkers. We used recurrence quantification analysis (RQA) to characterize properties of cyclical metabolic patterns of these metals. Regularity (determinism) and complexity (entropy) of elemental cycles was consistently reduced in ADHD for cobalt, lead, and vanadium (determinism: cobalt, β=−0.03,P=0.017; lead,β=−0.03,P=0.016; and vanadium,β=−0.03, P=0.01. Entropy: cobalt, β=−0.13,P=0.017; lead,β=−0.18,P=0.016; and vanadium,β=−0.15,P=0.008). Further, we found elemental pathways and dynamical features specific to ADHD vs ASD, and unique characteristics associated with ADHD/ASD combined presentation. Dysregulation of cyclical processes in elemental metabolism during prenatal and early postnatal development not only encompasses pathways shared by ADHD and ASD, but also comprise features specific to either condition.
Early medical events associated with autism spectrum condition (ASC)
Medical history of discordant twins and environmental etiologies of autism
The environmental contributions to autism spectrum disorder (ASD) and their informative content for diagnosing the condition are still largely unknown. The objective of this study was to investigate associations between early medical events and ASD, as well as autistic traits, in twins, to test the hypothesis of a cumulative environmental effect on ASD risk. A total of 80 monozygotic (MZ) twin pairs (including a rare sample of 13 twin pairs discordant for clinical ASD) and 46 dizygotic (DZ) twin pairs with varying autistic traits, were examined for intra-pair differences in early medical events (for example, obstetric and neonatal factors, first year infections). First, differences in early medical events were investigated using multisource medical records in pairs qualitatively discordant for ASD. The significant intra-pair differences identified were then tested in relation to autistic traits in the remaining sample of 100 pairs, applying generalized estimating equations analyses. Significant association of the intra-pair differences in the MZ pairs were found for the cumulative load of early medical events and clinical ASD (Z=−2.85, P=0.004) and autistic traits (β=78.18, P=0.002), as well as infant dysregulation (feeding, sleeping abnormalities, excessive crying and worriedness), when controlling for intelligence quotient and attention deficit hyperactivity disorder comorbidity. The cumulative load of early medical events in general, and infant dysregulation in particular, may index children at risk of ASD owing to non-shared environmental contributions. In clinical practice, these findings may facilitate screening and early detection of ASD.
Genetic variation and neurodevelopmental disorders
Copy Number Variation Analysis of 100 Twin Pairs Enriched for Neurodevelopmental Disorders
Hundreds of penetrant risk loci have been identified across different neurodevelopmental disorders (NDDs), and these often involve rare (<1% frequency) copy number variations (CNVs), which can involve one or more genes. Monozygotic (MZ) twin pairs are long thought to share 100% of their genomic information. However, genetic differences in the form of postzygotic somatic variants have been reported recently both in typically developing (TD) and in clinically discordant MZ pairs. We sought to investigate the contribution of rare CNVs in 100 twin pairs enriched for NDD phenotypes with a particular focus on postzygotic CNVs in MZ pairs discordant for autism spectrum disorder (ASD) using the Illumina Infinium PsychArray. In our sample, no postzygotic de novo CNVs were found in 55 MZ twin pairs, including the 13 pairs discordant for ASD. We did detect a higher rate of CNVs overlapping genes involved in disorders of the nervous system, such as a rare deletion affecting HNRNPU, in MZ pairs discordant and concordant for ASD in comparison with TD pairs (p = .02). Our results are in concordance with earlier findings that postzygotic de novo CNV events are typically rare in genomic DNA derived from saliva or blood, and suggests that the discordance of NDDs in our sample of twins is not explained by discordant CNVs. Still, studies investigating postzygotic variation in MZ discordant twins using DNA from different tissues and single cells and higher resolution genomics are needed in the future.
Alterations in resting state connectivity along the autism trait continuum: a twin study.
Autism spectrum disorder (ASD) has been found to be associated with alterations in resting state (RS) functional connectivity, including areas forming the default mode network (DMN) and salience network (SN). However, insufficient control for confounding genetic and environmental influences and other methodological issues limit the generalizability of previous findings. Moreover, it has been hypothesized that ASD might be marked by early hyper-connectivity followed by later hypo-connectivity. To date, only afew studies have explicitly tested age-related influences on RS connectivity alterations in ASD. Using a within-twin pair design (N= 150 twins; 8–23 years), we examined altered RS connectivity between core regions of the DMN and SN in relation to autistic trait severity and age in a sample of monozygotic (MZ) and dizygotic (DZ) twins showing typical development, ASD or other neurodevelopmental conditions. Connectivity between core regions of the SN was stronger in twins with higher autistic traits compared to their co-twins. This effect was significant both in the total sample and in MZ twins alone, highlighting the effect of non-shared environmental factors on the link between SN-connectivity and autistic traits. While this link was strongest in children, we did not identify differences between age groups for the SN. In contrast, connectivity between core hubs of the DMN was negatively correlated with autistic traits in adolescents and showed a similar trend in adults but not in children. The results support hypotheses of age-dependent altered RS connectivity in ASD, making altered SN and DMN connectivity promising candidate biomarkers for ASD.
Sex Differences Along the Autism Continuum: A Twin Study of Brain Structure
Females might possess protective mechanisms regarding autism spectrum disorder (ASD) and require a higher detrimental load, including structural brain alterations, before developing clinically relevant levels of autistic traits. This study examines sex differences in structural brain morphology in autism and autistic traits using a within-twin pair approach. Twin design inherently controls for shared confounders and enables the study of gene-independent neuroanatomical variation. N = 148 twins (62 females) from 49 monozygotic and 25 dizygotic same-sex pairs were included. Participants were distributed along the whole continuum of autism including twin pairs discordant and concordant for clinical ASD. Regional brain volume, surface area, and cortical thickness were computed. Within-twin pair increases in autistic traits were related to decreases in cortical volume and surface area of temporal and frontal regions specifically in female twin pairs, in particular regions involved in social communication, while only two regions were associated with autistic traits in males. The same pattern was detected in the monozygotic twin pairs only. Thus, non-shared environmental factors seem to impact female more than male cerebral architecture associated with autistic traits. Our results are in line with the hypothesis of a female protective effect in autism and highlights the need to study ASD in females separately from males.
Sex differences in brain structure: a twin study on restricted and repetitive behaviors in twin pairs with and without autism
Background: Females with autism spectrum disorder have been reported to exhibit fewer and less severe restricted and repetitive behaviors and interests compared to males. This difference might indicate sex-specific alterations of brain networks involved in autism symptom domains, especially within cortico-striatal and sensory integration networks. This study used a well-controlled twin design to examine sex differences in brain anatomy in relation to repetitive behaviors.
Methods: In 75 twin pairs (n= 150, 62 females, 88 males) enriched for autism spectrum disorder (n= 32), and other neurodevelopmental disorders (n= 32), we explored the association of restricted and repetitive behaviors and interests—operationalized by the Autism Diagnostic Interview-Revised (C domain) and the Social Responsiveness Scale-2 (Restricted Interests and Repetitive Behavior subscale)—with cortical volume, surface area and thickness of neocortical, sub-cortical, and cerebellar networks.
Results: Co-twin control analyses revealed within-pair associations between RRBI symptoms and increased thickness of the right intraparietal sulcus and reduced volume of the right orbital gyrus in females only, even though the mean number of RRBIs did not differ between the sexes. In a sub-sample of ASD-discordant pairs, increased thickness in association with RRBIs was found exclusively in females in the orbitofrontal regions, superior frontal gyrus, and intraparietal sulcus, while in males RRBIs tended to be associated with increased volume of the bilateral pallidum.
Limitations: However, due to a small sample size and the small difference in RRBI symptoms within pairs, the results of this exploratory study need to be interpreted with caution.
Conclusions: Our findings suggest that structural alterations of fronto-parietal networks in association with RRBIs are found mostly in females, while striatal networks are more affected in males. These results endorse the importance of investigating sex differences in the neurobiology of autism symptoms, and indicate different etiological pathways underlying restricted and repetitive behaviors and interests in females and males.
The Social Brain in Female Autism: A Structural Imaging Study of Twins
A female advantage in social cognition (SoC) might contribute to women’s underrepresentation in autism spectrum disorder (ASD). The latter could be underpinned by sex differences in social brain structure. This study investigated the relationship between structural social brain networks and SoC in females and males in relation to ASD and autistic traits in twins. We used a co-twin design in 77 twin pairs (39 female) aged 12.5 to 31.0 years. Twin pairs were discordant or concordant for ASD or autistic traits, discordant or concordant for other neurodevelopmental disorders or concordant for neurotypical development. They underwent structural magnetic resonance imaging and were assessed for SoC using the naturalistic Movie for the Assessment of Social Cognition. Autistic traits predicted reduced SoC capacities predominantly in male twins, despite a comparable extent of autistic traits in each sex, although the association between SoC and autistic traits did not differ significantly between the sexes. Consistently, within-pair associations between SoC and social brain structure revealed that lower SoC ability was associated with increased cortical thickness of several brain regions, particularly in males. Our findings confirm the notion that sex differences in SoC in association with ASD are underpinned by sex differences in brain structure.
Multimodal brain imaging in autism spectrum disorder and the promise of twin research
Current evidence suggests the phenotype of autism spectrum disorder to be driven by a complex interaction of genetic and environmental factors impacting onto brain maturation, synaptic function, and cortical networks. However, findings are heterogeneous, and the exact neurobiological pathways of autism spectrum disorder still remain poorly understood. The co-twin control or twin-difference design is a potentially powerful tool to disentangle causal genetic and environmental contributions on neurodevelopment in autism spectrum disorder. To this end, monozygotic twins discordant for this condition provide unique means for the maximum control of potentially confounding factors. Unfortunately, only few studies of a rather narrow scope, and limited sample size, have been conducted. In an attempt to highlight the great potential of combining the brain connectome approach with monozygotic twin design, we first give an overview of the existing neurobiological evidence for autism spectrum disorder and its cognitive correlates. Then, a special focus is made onto the brain imaging findings reported within populations of monozygotic twins phenotypically discordant for autism spectrum disorder. Finally, we introduce the brain connectome model and describe an ongoing project using this approach among the largest cohort of monozygotic twins discordant for autism spectrum disorder ever recruited.
Somatic health and ASC
The Association between Somatic Health, Autism Spectrum Disorder, and Autistic Traits
This study used a twin cohort to investigate the association of autism spectrum disorder (ASD) and autistic traits with somatic health. A total of 344 twins (172 pairs; mean age 15.56 ± 5.62 years) enriched for ASD and other neurodevelopmental conditions were examined. Medical history and current physical problems were collected with a validated questionnaire to determine twin’s somatic health. The Social Responsiveness Scale (SRS-2) was used to measure the participant’s severity of autistic traits. Identified somatic health issues with significant within-twin pair differences were tested in relation to both ASD diagnosis and autistic traits in a co-twin control model. Twins with ASD exhibited more neurological and immunological health problems compared to those without ASD (p = 0.005 and p = 0.004, respectively). The intra-pair differences of neurological conditions and SRS-2 score were significantly correlated in monozygotic twins differing for autism traits (r = 0.40, p = 0.001), while the correlation was not found for immunological problems. In addition, a conditional model for analysis of within-twin pair effects revealed an association between neurological problems and clinical ASD diagnosis (Odds ratio per neurological problem 3.15, p = 0.02), as well as autistic traits (β = 10.44, p = 0.006), after adjusting for possible effects of co-existing attention deficit hyperactivity disorder and general intellectual abilities. Our findings suggest that neurological problems are associated with autism, and that non-shared environmental factors contribute to the overlap for both clinical ASD and autistic traits. Further population-based twin studies are warranted to validate our results and examine in detailed the shared genetic and environmental contributions of neurological problems and ASD.
Familial confounding on the ability to read minds: A co-twin control study
Alterations in social cognition are hypothesized to underlie social communication challenges in autism spectrum disorder. However, the etiologic underpinnings driving this association, as well as the impact of other psychiatric conditions on the association, remain unclear. Using a co-twin control design, we examined n = 308 twins (mean age = 16.63; 46% females) with autism spectrum disorder, attention-deficit/hyperactivity disorder, affective disorders, or typical development using the Reading the Mind in the Eyes Test to operationalize social cognition ability. Clinical diagnosis of autism spectrum disorder, as well as the extent of quantitative autistic traits, as measured by parental reports using the Social Responsiveness Scale-2, predicted fewer expected responses on the Reading the Mind in the Eyes Test across the pairs. The association remained when adjusting for other diagnoses and IQ. In addition, male sex, lower age, and lower IQ predicted poorer performance on the Reading the Mind in the Eyes Test. The associations between autism and social cognition ability were lost within pairs in both the full sample and the monozygotic subsample. We conclude that the association between autism and social cognition across the sample highlights the importance of social cognition alterations in autism spectrum disorder when compared with other conditions. The attenuation of the association in the within-pair models indicate familial confounding, such as genes and shared environment, influencing both autism and social cognition.
Social Cognition in Autism and Other Neurodevelopmental Disorders: A Co-twin Control Study
Alterations in social cognition (SC) are hypothesized to underlie social communication and interaction challenges in autism spectrum disorder (ASD). The aetiological underpinnings driving this association remain unclear. We examined SC in 196 twins with ASD, other neurodevelopmental disorders or typical development using the naturalistic Movie for the Assessment of Social Cognition. Autism and its severity were assessed with the Autism Diagnostic Observation Schedule-2, and autistic traits with the Social Responsiveness Scale-2. Using within twin-pair regression models, controlling for age, sex, IQ, and unmeasured familial confounders such as genetic background and shared-environment, SC correlated with ASD diagnosis, autism severity, and autistic traits. Our findings highlight the importance of SC alterations in autism and suggest a non-shared environmental impact on the association.
That ASC is associated with alterations in sensory processing is well established. Results from RATSS indicate that this is also the case for people with ADHD. Results will be published shortly.
Global and local visual processing
Global and Local Visual Processing in Autism – a Co-twin-Control Study
Background: Autism Spectrum Disorder (ASD) is associated with altered global and local visual processing. However, the nature of these alterations remains controversial, with contradictory findings and notions ranging from a reduced drive to integrate information into a coherent ‘gestalt’ (“weak central coherence”= WCC) to an enhanced perceptual functioning (EPF) in local processing.
Methods: This study assessed the association between autism and global/local visual processing, using a large sample of monozygotic (MZ) and dizygotic (DZ) twins (N=290, 48%females, age=8–31 years). The Fragmented Pictures Test (FPT) assessed global processing, whereas local processing was estimated with the Embedded Figures Test (EFT) and the Block Design Test (BDT). Autism was assessed both categorically (clinical diagnosis), and dimensionally (autistic traits). Associations between visual tasks and autism were estimated both across the cohort and within-twin pairs where all factors shared between twins are implicitly controlled.
Results: Clinical diagnosis and autistic traits predicted a need for more visual information for gestalt processing in the FPT across the cohort. For clinical diagnosis, this association remained within-pairs and at trend-level even within MZ twin pairs alone. ASD and higher autistic traits predicted lower EFT and BDT performance across the cohort, but these associations were lost within-pairs.
Conclusions: In line with the WCC account, our findings indicate an association between autism and reduced global visual processing in children, adolescents and young adults (but no evidence for EPF). Observing a similar association within MZ twins suggests a non-shared environmental contribution.
Executive functioning in ADHD
On the role of non-shared environment for executive functioning in ADHD: a twin-differences design study
Introduction: The study of differences between monozygotic (MZ) twin pairs with respect to ADHD may provide novel leads to disentangle the environmental contribution driving its phenotypes.
Objectives: To examine non-shared environmental influences on executive function in dimensionally defined ADHD.
Methods: This study included 27 MZ twin pairs (7 female) aged 11–20 years being moderately to substantially discordant for ADHD traits as assessed by the Attention Problem (AP) scale of the Child Behavior Checklist/Adult Behavior Checklist. The twins completed the Wisconsin Card Sorting Test (WCST) for cognitive flexibility and the Tower Test (TT) for foresighted planning. Two statistical approaches were used to analyze the data. First, correlations between ADHD trait intra-pair differences and WCST and TT scores were calculated. Second, the significance of those intra-pair differences on WCST and TT, using ADHD as categorical variable in clinically discordant pairs, was tested.
Results: Both analysing strategies revealed a link between ADHD on one hand, and foresighted planning and inhibitory control on the other hand mediated by non-shared environmental factors. The first statistical approach yielded positive correlations between intra-pairs differences on the AP scale and intra-pair differences on two subscales of the TT: total rule violation (rs = 0·41) and rule-violation-per-item-ratio (rs = 0·38). Findings in categorically discordant pairs were consistent, showing within-pair differences on the same subtests (z-1·63, P = 0·05, one-tailed and z = −1·60, P = 0·05, one-tailed).
Conclusions: Findings confirm previous research suggesting ADHD to be a quantitative extreme on a continuum with executive functions being a cognitive marker of ADHD traits. Non-shared environmental factors appear to influence planning skills and inhibitory control.
Synesthesia is a condition where specific stimuli (such as sounds, letters or tastes) trigger additional sensory experiences such as colors or shapes. Research suggest that synesthesia is more common in people with ASC, and might be correlated with advantages such as better memory and increased creativity. In a sub-sample of twins from the RATSS project, we found that twins with higher autistic traits in the attention to details domain score more like a synesthete compared to their co-twins on an objective synesthesia test. These results will be published shortly. We are also investigating the link between synesthesia and ASC in other twin cohorts - read more about this project here.
This project studies the causes for obsessive-compulsive disorder (OCD). Read more on this project.
Camouflaging, gender differences, and ASC in girls and women
Previous research indicates that ASC may present differently among males and females. Potential gender differences in autism are important to study in order to gain knowledge of the differing experiences among autistic people and to better tailor support. In RATSS we are currently investigating gender differences in eating problems and camouflaging among autistic females and males. More information will be available when these results are published.
Minor physical anomalies in neurodevelopmental disorders: a twin study
Background: Minor physical anomalies (MPAs) are subtle anatomical deviations in one’s appearance and may suggest altered embryogenesis. MPAs have been shown to be more common in neurodevelopmental disorders (NDDs) compared with typical development. Still, further studies are needed on MPAs in NDDs, especially using twins to adjust for confounding familial factors.
Methods: Clinical assessments were conducted on 116 twins (61 NDD, 55 controls) from 51 monozygotic and 7 dizygotic pairs to examine MPAs and their association with DSM‑5 defined NDDs. Additionally, the relationship between the number of MPAs within twins by zygosity was investigated.
Results: Within the cohort sample, a specific association was found between MPAs and autism spectrum disorder (ASD) diagnosis (crude odds ratio= 1.29, p= .047; adjusted odds ratios= 1.26–1.33, adjusted p values= .032–.073) and autistic traits (crude β= 3.02, p= .002; adjusted β= 2.28, p= .019), but not NDDs in general or ADHD, nor within‑pairs. Identified MPAs in ASD included overweight, hypermobility, pes planus, straight eyebrows, vision impairment, arachnodactyly/long toes, long eyelashes, and microtia. The number of MPAs within all monozygotic pairs was highly correlated (r= .88, p < .001).
Conclusion: MPAs are more frequent in participants with ASD and may be influenced by genetics. The value of MPAs for (early) detection should be further explored, as they might index individuals at increased risk for ASD in particular.
Clinical versus automated assessments of morphological variants in twins with and without neurodevelopmental disorders
Physical examinations are recommended as part of a comprehensive evaluation for individuals with neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and attention–deficit/hyperactivity disorder. These examinations should include assessment for morphological variants. Previous studies have shown an increase in morphological variants in individuals with NDDs, particularly ASD, and that these variants may be present in greater amounts in individuals with genetic alterations. Unfortunately, assessment for morphological variants can be subjective and time-consuming, and require a high degree of clinical expertise. Therefore, objective, automated methods of morphological assessment are desirable. This study com-pared the use of Face2Gene, an automated tool to explore facial morphological variants, to clinical consensus assessment, using a cohort of N= 290 twins enriched for NDDs (n= 135 with NDD diagnoses). Agreement between automated and clinical assessments were satisfactory to complete (78.3–100%). In our twin sample, individuals with NDDs did not have greater numbers of facial morphological variants when compared to those with typical development, nor when controlling for shared genetic and environmental factors within twin pairs. Common facial morphological variants in those with and without NDDs were similar and included thick upper lip vermilion, abnormality of the nasal tip, long face, and up slanted palpebral fissure. We conclude that although facial morphological variants can be assessed reliably in NDDs with automated tools like Face2Gene, clinical utility is limited when just exploring the facial region. Therefore, currently, automated assessments may best complement, rather than replace, in-person clinical assessments.
Variable neurodevelopmental and morphological phenotypes of carriers with 12q12 duplications
Background: Variable size deletions affecting 12q12 have been found in individuals with neurodevelopmental disorders (NDDs) and distinct facial and physical features. For many genetic loci affected by deletions in individuals with NDDs, reciprocal du-plications have been described. However, for the 12q12 region, there are no detailed descriptions of duplication cases in the literature.
Methods: We report a phenotypic description of a family with monozygotic twins diagnosed with NDDs, carrying a 9 Mb duplication at 12q12, and five other individuals with overlapping duplications ranging from 4.54 Mb up to 15.16 Mb.
Results: The duplication carriers had language delays, cognitive delays, and were diagnosed with autism spectrum disorder. Additionally, distinct facial features (e.g., high foreheads, deeply set eyes, short palpebral fissures, small ears, high nasal bridges, abnormalities of the nose tip, thin lips), large feet, and abnormalities in the digits were noted. We also describe incomplete penetrance of the NDD phenotypes among the individuals with 12q12 duplication.
Conclusion: This case series expands our knowledge on this rare genetic aberration and suggests that large 12q12 duplications may increase the risk for developing NDDs.
2D:4D Ratio in Neurodevelopmental Disorders: A Twin Study
The second to fourth digit (2D:4D) ratio is of interest in autism spectrum disorder (ASD). Studies on the relationship of this ratio with other neurodevelopmental disorders (NDDs) are lacking. Investigating the association between the ratio and NDDs in twins can provide insight into genetic and/or environmental factors driving the ratio. Hand images were collected in N = 238 twins with NDDs or typical development from 70 monozygotic and 49 dizygotic pairs to examine ratios and their associations to DSM-5 defined categorical NDDs, autistic traits, zygosity, and sex. There were small associations for males between the ratios and any NDD and ADHD diagnoses. Males had lower ratios than females. Future studies exploring the ratio alongside physical anomalies could provide etiological insight into NDDs.
Derivation of human iPS cell lines from monozygotic twins in defined and xeno free conditions
Human induced pluripotent stem (hiPS) cell lines CTRL-9-II and CTRL-10-I were derived from healthy monozy- gotic twin donors using non-integrating RNA based Sendai virus reprogramming and cultured in a xeno-free chemically defined condition. The established hiPS cell lines, CTRL-9-II and CTRL-10-I, are karyotypically normal, free from reprogramming vectors, display endogenously expression of pluripotency factors at levels similar to embryonic stem cells. The generated iPS cell lines demonstrate pluripotency by passing bioinformatics assay PluriTest and by embryonic body assay.
Some of the twins who participated RATSS have been invited to participate in additional cognitive testing and assessments (e.g. eye-tracking) in the Longitudinal European Autism Project (LEAP), a collaboration between research groups in several European countries.
EU-AIMS Longitudinal European Autism Project (LEAP): the autism twin cohort
EU-AIMS is the largest European research program aiming to identify stratification biomarkers and novel interventions for autism spectrum disorder (ASD). Within the program, the Longitudinal European Autism Project (LEAP) has recruited and comprehensively phenotyped a rare sample of 76 monozygotic and dizygotic twins, discordant, or concordant for ASD plus 30 typically developing twins. The aim of this letter is to complete previous descriptions of the LEAP case-control sample, clinically characterize, and investigate the suitability of the sample for ASD twin-control analyses purposes and share some ‘lessons learnt.’ Among the twins, a diagnosis of ASD is associated with increased symptom levels of ADHD, higher rates of intellectual disability, and lower family income. For the future, we conclude that the LEAP twin cohort offers multiple options for analyses of genetic and shared and non-shared environmental factors to generate new hypotheses for the larger cohort of LEAP singletons, but particularly cross-validate and refine evidence from it.
Social brain activation during mentalizing in a large autism cohort: the Longitudinal European Autism Project
Dissecting the Heterogeneous Cortical Anatomy of Autism Spectrum Disorder Using Normative Models
Investigating the factors underlying adaptive functioning in autism in the EU-AIMS Longitudinal
European Autism Project
Altered Connectivity Between Cerebellum, Visual, and Sensory-Motor Networks in Autism Spectrum Disorder: Results from the EU-AIMS Longitudinal European Autism Project
EU-AIMS Longitudinal European Autism Project (LEAP): the autism twin cohort
The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation
The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders
Identification and validation of biomarkers for autism spectrum disorders