Intellectual Disability (ID) is one of the most common neurodevelopmental disorders, affecting between 1.5-2% of individuals in the general population. This pathology has a serious impact on the affected individuals, their families and also on the health care system. Understanding the genetic mechanisms implicated in the disease is challenging, since ID includes a wide spectrum of possible underlying disorders and the genetic variants determining the disease are highly heterogeneous, requiring the application of different approaches and techniques, from cytogenetic analysis to the application of most recent NGS strategies. In the last decades, big steps forward have been done in the search of the genetics determinants for ID, however today less then half of the patients receive a molecular diagnosis. Moreover, the continue reporting of new ID-genes suggests that many of the genetic variants causing ID still need to be discovered and understood. The aim of the thesis is to identify new genes and genetic variants involved in ID, with the use of diverse approaches and methodologies.
The first stage of the study has been the screening of a cohort of nonsyndromic ID patients with a gene-panel specific for non-syndromic ID. This approach has led to the discover of 6 novel putative mutations and, when possible, the impact of the variation has been evaluated in silico, with an analysis of the protein structure. The screening also led to the selection of two patients that underwent to whole-exome sequencing analysis with the aim to identify the causative variant beyond the most common genes for the disease. Notably, we have discovered 2 X-linked mutations having likely a pathogenetic role. One is a missense mutation in CLCN4, a gene member of the chloride channel family that only recently has been demonstrated to cause ID. Another missense mutation has been found in ALG13 gene that has been associated with X-linked non-syndromic ID only once but without a clear explanation of its functioning.
The second part of the thesis concerns the investigation on genetic variants having a mild impact on the phenotype. We performed a Runs of Homozygosity study to investigate the role of distant inbreeding in ID. The analysis has revealed that the global amount of homozygosity and the number of homozygous stretches are associated with the degree of the impairment. Finally, we also designed an association study for the Y chromosome to investigate the presence of variants implicated in the development of cognitive function in this genomic region. We analysed the general cognitive function measured in 5 cross-sectional cohorts but did not find evidence for an association on the Y chromosome.
