Bidirectional genetic overlap between autism spectrum disorder and cognitive traits.

Autism spectrum disorder (ASD) is a highly heritable condition with a large variation in cognitive function. Here we investigated the shared genetic architecture between cognitive traits (intelligence (INT) and educational attainment (EDU)), and risk loci jointly associated with ASD and the cognitive traits. We analyzed data from genome-wide association studies (GWAS) of INT (n = 269,867), EDU (n = 766,345) and ASD (cases n = 18,381, controls n = 27,969). We used the bivariate causal mixture model (MiXeR) to estimate the total number of shared genetic variants, local analysis of co-variant annotation (LAVA) to estimate local genetic correlations, conditional false discovery rate (cond/conjFDR) to identify specific overlapping loci. The MiXeR analyses showed that 12.7k genetic variants are associated with ASD, of which 12.0k variants are shared with EDU, and 11.1k are shared with INT with both positive and negative relationships within overlapping variants. The majority (59-68%) of estimated shared loci have concordant effect directions, with a positive, albeit modest, genetic correlation between ASD and EDU (rg = 0.21, p = 2e-13) and INT (rg = 0.22, p = 4e-12). We discovered 43 loci jointly associated with ASD and cognitive traits (conjFDR<0.05), of which 27 were novel for ASD. Functional analysis revealed significant differential expression of candidate genes in the cerebellum and frontal cortex. To conclude, we quantified the genetic architecture shared between ASD and cognitive traits, demonstrated mixed effect directions, and identified the associated genetic loci and molecular pathways. The findings suggest that common genetic risk factors for ASD can underlie both better and worse cognitive functioning across the ASD spectrum, with different underlying biology.

Age-related changes in behavioural and emotional problems in Smith-Magenis syndrome measured with the Developmental Behavior Checklist.

Smith-Magenis syndrome (SMS) is a genetic syndrome most often caused by a deletion on chromosome 17 or more rarely by a mutation in the retinoic acid-induced 1 gene. The aim of this study was to investigate the Developmental Behavior Checklist (DBC) profile of persons with SMS and the associations between behavioural and emotional problems, age, gender, adaptive behaviour and autism symptomatology. Twenty-eight persons with SMS were represented by their parents in this study. DBC Total scores are reduced with age, but they still show a mean that is clearly above the cut-off of 46. The differences between the age groups <9 years and 9-17 years (p = 0.024) and between the age groups <9 years and >18 years (p = 0.007) are significant. We found a significant decrease in behavioural and emotional problems with age in SMS. We did not find a relationship between adapted behaviour and communication and behavioural and emotional problems.

Parental experiences with behavioural problems in Smith-Magenis syndrome: The need for syndrome-specific competence.

The experience of having a rare disorder was summarised in a large study as 'falling outside the vast field of knowledge of the professionals'. Parents (31 mothers and 17 fathers) of 32 persons with Smith-Magenis syndrome (SMS) participated in this study. A phenomenological approach was used to analyse the data into topics and themes. Four themes emerged: behavioural challenges displayed, parents' strategies for meeting the challenging behaviours, parents' experiences of their own competence and parents' experiences of professionals' competence and understanding regarding children with SMS and their behaviour challenges. We found that parents of children with SMS experience that they are exposed to severe challenging behaviours from their child. The parents believe that they experience more misunderstandings with professionals and that the challenging behaviours increase because there are some specific characteristics of SMS that professionals are not aware of or do not consider in their support services.

Reversed gender ratio of autism spectrum disorder in Smith-Magenis syndrome.

Background: A substantial amount of research shows a higher rate of autistic type of problems in males compared to females. The 4:1 male to female ratio is one of the most consistent findings in autism spectrum disorder (ASD).Lately, the interest in studying ASD in genetic disorders has increased, and research has shown a higher prevalence of ASD in some genetic disorders than in the general population.Smith-Magenis syndrome (SMS) is a rare and complex genetic syndrome caused by an interstitial deletion of chromosome 17p11.2 or a mutation on the retinoic acid induced 1 gene. The disorder is characterised by intellectual disability, multiple congenital anomalies, obesity, neurobehavioural abnormalities and a disrupted circadian sleep-wake pattern. Methods: Parents of 28 persons with SMS between 5 and 50 years old participated in this study. A total of 12 of the persons with SMS were above the age of 18 at the time of the study. A total of 11 came from Sweden and 17 were from Norway.We collected information regarding the number of autism spectrum symptoms using the Social Communication Questionnaire (SCQ) and the Social Responsiveness Scale (SRS). Adaptive behaviour was also measured using the Vineland Adaptive Behavior Scale II. The level of intellectual disability was derived from a review of the medical chart. Results: We found significant gender differences in ASD symptomatology using the SCQ and SRS questionnaires. We found approximately three females per male above the SCQ cutoff. The same differences were not found in the intellectual level and adaptive behaviour or for behavioural and emotional problems.Gender had an independent contribution in a regression model predicting the total SCQ score, and neither the Vineland Adaptive Behavior Scale II nor the Developmental Behaviour Checklist had an independent contribution to the SCQ scores. Conclusion: We found a clear reversed gender difference in ASD symptomatology in persons with SMS. This may be relevant in the search for female protective factors assumed to explain the male bias in ASD.

A structured assessment of motor function, behavior, and communication in patients with Wolf-Hirschhorn syndrome.

The present study aimed to increase the knowledge about Wolf-Hirschhorn syndrome (WHS), especially concerning motor function, autism spectrum disorders (ASD), and adapted behavior, but also regarding clinical symptoms in general. Motor function was evaluated via systematic observation. Standardized assessments such as the Vineland Adapted Behavior Scales II (VABS II), the Social Communication Questionnaire (SCQ), and the Child Behavior Checklist (CBCL) or Adult Behavior Checklist (ABCL) were used for the behavioral assessment. In total, two males and eight females between one and 48 years of age with a genetically confirmed diagnosis of WHS and their parents participated in this study. Deletion sizes were known for seven of the ten patients and varied between 55 Kb and 20 Mb. The chromosome coordinates were known for six of them, and none of those had the same break points in their deletion. The main finding in this study was that patients with WHS may have a better outcome regarding motor skills and expressive communication than previously described. We could confirm the main medical findings described earlier, but found also a population with a less severe dysmorphology, fewer congenital malformations, and fewer medical challenges than expected. Sleep problems may persist into adulthood and need a more thorough investigation. Research on possible indications of ASD is strongly needed for targeted interventions. In conclusion, a more thorough assessment of communication, possible ASD, and sleep in larger groups of patients with WHS are needed to confirm and further investigate the findings from this study and to provide more targeted interventions for WHS patients.

A structured assessment of motor function and behavior in patients with Kleefstra syndrome.

The present study aimed to further our understanding of Kleefstra syndrome, especially regarding motor function and behavioral characteristics. In total, four males and four females between two and 27 years of age with a genetically confirmed diagnosis of Kleefstra syndrome and their parents participated in this study. Four patients had 9q34.3 deletions that caused Euchromatin Histone Methyl Transferase 1 (EHMT1) haplo-insufficiency, and four patients harbored EHMT1 mutations. The motor function was evaluated via systematic observation. Standardized assessments such as the Vineland Adapted Behavior Scales II (VABS II), the Social Communication Questionnaire (SCQ) and the Child or Adult Behavior Checklist (CBCL, ABCL) were used for the behavioral assessment. All patients showed a delayed developmental status. Muscular hypotonia and its manifestations were present in all patients, regardless of their age. The mean values for all VABS II domains (communication, socialization, daily living skills, and motor skills) were significantly lower than the mean of the reference population (p < 0.001), but similar to other rare intellectual disabilities such as Smith-Magenis syndrome and Angelman syndrome. The results from the SCQ indicated that all patient values exceeded the cut-off value, suggesting the possibility of autism spectrum disorder. The behavioral and emotional problems assessed by CBCL and ABCL were less frequent. In conclusion, patients with Kleefstra syndrome present with a broad range of clinical problems in all age groups and are therefore in need of a multidisciplinary follow-up also after their transition into adulthood.