Molecular and Clinical Characterization of Syndromes Associated With Intellectual Disability

Sammanfattning: Intellectual disability (ID) affects approximately 1-3% of the population and is defined as having an IQ below 70 as well as a significant limitation in adaptive behavior.The implementation of chromosomal microarrays (CMA) into the field of clinical genetics has revolutionized the ability to find genetic aberrations responsible for different genetic disorders. Importantly. these technologies have allowed several new microdeletion and microduplication aberrations to be identified that otherwise would have escaped detection using more conventional methods. Finding the genetic etiology of a syndrome and its association to the phenotype is paramount to better health care, provision of tailored therapy, presymptomatic screening, accurate prognosis, recurrence risk evaluation and in some cases prenatal testing.Despite the plethora of new information available, there are still a number of clinical and genetic features we do not fully understand.The aim of this work was to identify regions and syndromes associated with ID by CMA analysis and to make a detailed clinical description of the affected patients’ phenotype.In paper I we studied the 22q11.2 duplication syndrome and presented two familial cases with a description of both their genotype and phenotype. Additionally, 36 cases harboring the duplication were reviewed to further delineate the phenotype of the syndrome.In paper II, we revealed two unrelated patients with a deletion at 6q14.1-q15 and a distinct phenotype. Together with one previously reported patient our study suggests that a novel, clinically recognizable microdeletion syndrome exists in these patients.In paper III the phenotype and genotype of six unrelated patients with partially overlapping microdeletions at 10p12.31-p11.21 were described. Taken together with a previously reported patient we propose that these findings represent a new contiguous gene syndrome.In paper IV, two sisters; one presenting with two tandem interstitial duplications and the other a large deletion over the same region (6q13-q16) were reported. The reason for the CNVs was a maternal de novo translocation. This is the first case describing the genotype and phenotype of this duplicated region at 6q13-q16.In conclusion, four different genetic aberrations involved in the etiology of ID and their corresponding phenotypes and candidate genes have been characterized.