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Severe intellectual disability (ID) affects about 0.5% of the population and is accompanied by significant comorbidity. It is largely of genetic origin with many individually rare genes accounting for less than 0.5% of patients each.
Despite an enormous progress in diagnostic yield since the raise of whole exome sequencing during the last 5 years, more than half of patients remain currently without diagnosis, which hampers proper disease management and genetic counselling. Recent studies using whole genome sequencing evidenced a much higher diagnostic yield in known disease genes through improved variant detection in severe ID and indicated a relevant role of de novo variants in non-coding regulatory regions in related disorders such as autism and schizophrenia.
In contrast to unspecific ID, patients with severe ID and intractable seizures, commonly referred to as epileptic encephalopathy (EE) have been studied less well and diagnostic yields in known disease genes have been relatively low.
Through our previous exome sequencing studies in patients with unspecific severe ID as well as in EE, we identified 18 novel candidate genes. In order to further increase the understanding of the genetic and molecular mechanisms causing severe developmental disorders we aim to confirm at least two of our novel candidate genes by further in-depth genetic and functional studies. We also aim to study cellular, molecular and electrophysiological properties of patient iPSC-derived neurons harboring a variety of mutations to improve genotype-phenotype correlation and identify readouts to ease future functional and interventional studies.
Finally, we hope to pave the way for increased knowledge of the underlying disease mechanisms to study novel therapeutic approaches in the future, eventually enabling better care for patients with severe neurodevelopmental disorders.
Novel disease genes recently derived from this and related projects:
Funded by SNSF.
