Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically

Examining neurodevelopmental problems in 15q11.2 ( BP1‐BP2 ) copy number variation carriers at ages 9/12 and 18 in a Swedish twin sample

Background: Several copy number variations (CNVs) are associated with increased risk for neurodevelopmental and psychiatric disorders. The CNV 15q11.2 (BP1‐BP2) deletion has been associated with learning difficulties, attention deficit hyperactivity disorder (ADHD), epilepsy, and brain morphology; however, many carriers present mild or no symptoms. Carrying the reciprocal duplication does not seem to confer risk for these disorders or traits. Our aim was to examine the impact of carrying either 15q11.2 deletion and reciprocal duplication on neurodevelopmental problems in a population‐based sample of children. Methods: Twins with genotype and phenotype information in the Child and Adolescent Twin Study in Sweden (CATSS) were included (N = 12,040). We included measures of neurodevelopmental problems (NDPs), including learning problems, from the questionnaire Autism–Tics, ADHD, and other Comorbidities inventory (A‐TAC) at age 9/12, ADHD and autism spectrum disorder (ASD) questionnaires at age 18, as well as information about lifetime psychiatric diagnoses and epileptic seizures. We tested the association between these phenotypic measurements and carrying the 15q11.2 deletion, the reciprocal duplication, and other CNVs with previously reported strong associations with neurodevelopmental and psychiatric disorders (i.e., psychiatric CNVs). Results: We identified 57 carriers of the 15q11.2 deletion, 75 carriers of the reciprocal duplication, and 67 carriers of other psychiatric CNVs. We did not find an increased risk for NDPs or psychiatric diagnoses in the 15q11.2 deletion carriers. For 15q11.2 duplication carriers, we found an increased risk for math learning problems and fewer self‐reported ADHD symptoms at age 18 but not for other NDPs. In line with previous studies, we found an increased risk of NDPs and other evaluated phenotypes in carriers of psychiatric CNVs. Conclusions: Our results support previous findings that carrying 15q11.2 deletion does not have a large effect on NDPs in children

Pupil size and pupillary light reflex in early infancy: heritability and link to genetic liability to schizophrenia

Background: Measures based on pupillometry, such as the pupillary light reflex (PLR) and baseline pupil size, reflect physiological responses linked to specific neural circuits that have been implicated as atypical in some psychiatric and neurodevelopmental conditions. Methods: We investigated the contribution of genetic and environmental factors to the baseline pupil size and the PLR in 510 infant twins assessed at 5 months of age (281 monozygotic and 229 dizygotic pairs), and its associations with common genetic variants associated with neurodevelopmental (autism spectrum disorder and attention deficit hyperactivity disorder) and mental health (bipolar disorder, major depressive disorder and schizophrenia) conditions using genome-wide polygenic scores (GPSs). Results: Univariate twin modelling showed high heritability at 5 months for both pupil size (h2 = .64) and constriction in response to light (h2 = .62), and bivariate twin modeling indicated substantial independence between the genetic factors influencing each (rG = .38). A statistically significant positive association between infant tonic pupil size and the GPS for schizophrenia was found (β = .15, p = .024), while there was no significant association with the GPS for autism or any other GPSs. Conclusions: This study shows that some pupil measures are highly heritable in early infancy, although substantially independent in their genetic etiologies, and associated with common genetic variants linked to schizophrenia. It illustrates how genetically informed studies of infants may help us understand early physiological responses associated with psychiatric disorders which emerge much later in life

Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium’s ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity

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

DYX1C1 is required for axonemal dynein assembly and ciliary motility

DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2–4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1 c.T2A start-codon mutation recovered from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also caused laterality and ciliary motility defects. In humans, we identified recessive loss-of-function DYX1C1 mutations in 12 individuals with PCD. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans showed disruptions of outer and inner dynein arms (ODAs and IDAs, respectively). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU). Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4)

Twin research in autism spectrum disorder

© 2017 by Taylor & Francis Group, LLC. Autism spectrum disorder (ASD) is a neurodevelopmental condition of multifactorial origin. Aside from clinically relevant ASD phenotypes qualifying for a categorical diagnosis, data increasingly support the notion of broader/extended phenotypes and traits of ASD that are continuously distributed in the general population, with variation in ASD traits determined by factors overlapping with the clinical phenotypes. Earlier twin studies confirmed repeatedly the genetic causes for ASD, with only modest environmental influences. Thus, ASD is considered one of the most heritable of psychiatric conditions with a heritability estimates between 80% and 90%. However, recent twin studies have suggested a stronger environmental influence on ASD etiologies. This chapter gives a short theoretical background on the basics of behavioral genetics and twin designs, summarizes the contribution of twin research to the knowledge of ASD etiologies, and discusses areas of interest for future twin research within the field of ASD