Genetic Aspects of Autism Spectrum Disorders. Summary of the Doctoral Thesis

Abstract

Autism spectrum disorders (ASD) are the common early children’s mental health disorder that can be a cause of severe child’s disability. The inheritance model of ASD is complex and complicated involving both environmental factors and genetic risk factors. At the conducted study, the involved group of ADS patients does not represent all Latvian ASD population. It could be the limiting factor of the population due to which ASD prevalence parameters have not been calculated because a representative ASD sample has not been created in which all ASD cases diagnosed in Latvia would be collected. The objective data on the real situation in Latvia are not available because no ASD epidemiologic studies have been performed, as well as no united register has been created containing information on all diagnosed ASD cases in Latvia. The situation is compounded by the lack of the single diagnostic system, as well as because no guidelines have been developed for use of objective ASD diagnostics appropriate for the international practice throughout the country, not only in separate mental health centers. The early ADS diagnostics is still complicated and delayed in Latvia. These data are unique because it is the first ASD study in Latvia. The study data do not reflect information about all ASD cases in Latvia but they allow judging the general ASD trends. Patients with syndromic autism were excluded from the study and further ASD patients with non-syndromic or idiopathic autism were analyzed. In this study, the ASD sample was created containing information on physical and mental development of the ASD patients, ASD course and family anamnesis. A database describing phenotype and genotype has been formed and anthropometric parameters were analyzed. It is found in the study that the ASD patients have increased head circumference and weight comparing to the standard population. The frequency of mental retardation of different degree is 80.66%, the frequency of language disorders is 98.66% and the frequency of epileptic seizures is 5.33%. Epileptic seizures were more common in the patients with severe mental retardation (p = 0.009). Association between four genetic markers of the chromosome 11th and 15th and ASD was analyzed. A statistically significant association between ASD and SNP rs11212733 (p = 0.008) that is localized in the chromosomal locus 11q22.3 between gene DDX10 and EXPH5. The choice of non-medication and medication therapy was evaluated, efficiency and most common adverse reactions of the second-generation antipsychotics Risperidone were determined in association with the selected pharmacogenetic marker. It is found that CYP2D*4 and CYP2D*41 are not informative because they are not associated with the efficiency and adverse reactions of Risperidone. Accordingly to autosomal dominant inheritance model, a family with Asperger’s syndrome in two generations was chosen and complete exome sequencing for three family members was performed to find the possible candidate genes of ASD that might be involved in the ASD etiology. When performing sequencing of the selected potential candidate genes by Sanger’s method a pathogenic variant of KCNH6 gene was identified that might be the possible candidate gene of ASD. Practical recommendations for family doctors, pediatricians, child neurologists and psychiatrists were created for early ASD diagnostics.