Defining the role of genetic burden in intellectual disability

General Background
This research project focuses on how the combinations of genetic mutations can result in Intellectual Disability.

The overall aims of this project are:
  • Create and apply methods to identify and interpret co-occurring pathogenic variants.
  • Study the phenotypic impact of rare inherited genetic variants associated to intellectual disability using a combination of genetic variant analysis as well as state of the art facial phenotyping.

Project description
Effective genetic diagnosis, and the identification of novel genes causing intellectual disability (ID), is an ongoing task. We have recently shown that rare sporadic de novo genetic mutations cause 56% of severe ID cases and an estimated 2000 genes may be linked to ID. In a further 15% of cases rare inherited mutations are identified which are predicted to be pathogenic, however their role in disease is unclear. Traditionally, genetic studies are based on single-gene or single large variant analyses. However these analysis methods are insufficient for understanding the complicated genetic interactions involved in heterogeneous diseases such as ID with a large mutational target. In pilot data focused on rare duplications and deletions I could predict that 57% of rare inherited deletions and duplications contribute to a patient's phenotype in ID. In addition, an increase in genetic burden results in a more severe patient phenotype, most notably facial dysmorphy. In this project we will systematically investigate the genetic burden in ID patients through combined genomewide analysis of large and small genetic variants. Recent developments in whole exome and genome sequencing now allow such analyses in large cohorts of ID patients. For this we will develop and apply novel data analysis methods to study the impact of co-occurring variants. In a study involving de novo structural variants we have recently shown that 20% of pathogenic genes are involved in a single highly-connected gene network. And that rare genetic variants inherited from apparently unaffected parents can have a significant impact on a patient's phenotype. Understanding fundamental questions surrounding partial penetrance of genomic variants requires detailed study of patient and parent phenotypes. We hypothesize that a significant proportion of ID cases can be explained by a two-hit model in which rare inherited mutations cause ID when co-occurring with another damaging genetic variant affecting the same gene network. At present, the impact of genetic burden in ID is poorly understood due to limitations in data analysis methods and a lack of quantitative phenotypes.

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