The genetics of autism spectrum disorder: family based translational research on rare variants

Despite the great advances in recent years, there are still many gaps in the knowledge on the genetic etiology of autism spectrum disorder (ASD) and counseling for ASD has become one of the biggest challenges in clinical genetics. Since many novel variants are being identified, translational genetic research should bridge the gap between the discovery of ASD susceptibility variants and the actual clinical utility for patients and families. Therefore, this project mainly focused on family based research strategies to find new genes and loci involved in the etiology of ASD, to study CNV profiles that may confer susceptibility to ASD and to determine the clinical validity of known genetic risk variants for ASD. For one thing, unique chromosomal aberrations that occurred de novo and in combination with a pronounced ASD phenotype are of interest. Although such variants are very rare, they can broaden the knowledge on the genetic etiology of ASD by the identification of new genes. Consequently, the current study included the analysis of an individual with syndromic ASD and a unique de novo translocation. The exact breakpoints were determined by a combination of positional cloning techniques and next generation sequencing, including the implementation of targeted locus amplification. As a result, we could identify a role for ZNF462 mutations in the etiology of ASD. Further, copy number variants (CNVs) contribute to the ASD phenotype in about 10-15% of patients, many of them having syndromic ASD. However, less is known on the contribution of CNVs in patients with non-syndromic ASD. Therefore, 158 well-characterized families selected though probands with a pronounced autism phenotype, non-syndromic ASD and normal to borderline intelligence were screened for CNVs at a high resolution. To that end, a method for filtering CNVs called from a high resolution array was developed and validated. Furthermore, when comparing the CNV profiles of ASD individuals and unaffected siblings, ASD individuals were found to carry more genes in duplications and more inherited deletions involving regulatory regions. These statistical findings were illustrated by the identification of CNVs that might contribute to ASD in specific families, providing further evidence for a contribution of variants of yet unknown significance to non-syndromic ASD. Finally, case based reasoning for 8p21.3 deletions, which were identified as a possible new susceptibility locus in the previous analysis, allowed to conclude that these deletions are rare causes of non-syndromic ASD. Case based reasoning and comparison of patient and family specific characteristics is important to determine the actual contribution of the variant to the ASD phenotype, particularly for ASD risk variants that are often inherited from an unaffected parent. As an example and proof of principle for genotype-phenotype correlation studies this part of the project focused on intragenic deletions of the neurexin 1 (NRXN1) gene. Hence, we analyzed clinical and molecular data of 629 heterozygous NRXN1 deletions reported in literature, including deletions in controls, probands and carrier relatives, as well as 43 new deletions identified in our center. These analyses allowed to calculate population prevalences, penetrances and to distinguish distinct parts in the NRXN1 gene that relate to specific clinical considerations. Finally, also single nucleotide variants (SNVs) can cause ASD, but their exact contribution is even harder to interpret. Therefore, we provided 1,894 samples of well-characterized individuals with ASD for targeted sequencing of 208 candidate genes for neurodevelopmental disorders to gain insight in the contribution of SNVs to ASD in our population. To date, segregation studies were performed in a subset of families to enhance translational research. The latter contributed to the identification of a number of ASD candidate genes including IQGAP3 and NFIA.

Jaar van publicatie:2018

Toegankelijkheid:Closed