Intellectual disability (ID) is a neurodevelopmental disorder that affects 1-3% of the population and represents a major public health issue. ID is highly heterogeneous, regarding the severity of its manifestation, the possible comorbid symptoms, as well as its etiology. While hundreds of genes have already been associated with ID, the genetic causes of many cases still remain elusive. We have decided to use whole exome sequencing (WES) to unravel the genetic causes of unsolved syndromic ID in 23 families.
During my doctorate, I worked in collaboration with clinicians from Lithuania and Italy who collected clinical data of families for which microarrays and Fragile-X tests were negative. While ID was diagnosed for every patient I studied, the presence of additional symptoms made each family a particular case that I had to analyze individually. Candidate variants identified by WES were validated via functional analysis as well as clinical data collection of similar cases through international collaborations.
My work led to the discovery of a new ID syndrome characterized by mesomelic dysplasia, horseshoe kidney and encephalopathic epilepsy, and the description of the underlying molecular mechanism. De novo missense variants in the degron motif of AFF3 are gain-of-function through an accumulation of the encoded protein. This hypothesis is supported by molecular and animal models analysis.
Moreover, I identified a yet unreported de novo variant in a known ID gene, PIK3R2, in a boy with severe encephalopathy, explaining the molecular mechanism via 3D modeling. I also broadened the phenotypical description of the Aicardi-Goutières syndrome, describing the first inflammatory myopathy case associated with a homozygous missense variant in TREX1. I participated in the description of two new syndromes associated with variants in KIAA1109 and MAST1. As exome sequencing of the other families allowed us to identify likely-pathogenic variants or variants of uncertain significance, gathering clinical data of similar cases and functional evidences are warranted.
Overall, my work enabled us to report a genetic diagnosis to multiple patients and their families, providing opportunities to improve their family planning, clinical care and follow-up. Ultimately, a better delineation of the pathological mechanisms involved in neurodevelopmental disorders such as ID will help identifying new therapeutic targets.