Integrating clinical diagnostics with interventional genetics for neurodevelopmental disorders

Interventional genetics (IG) refers to the development of therapies aimed at treating the underlying genetic cause of disease. Diagnostic sequencing has advanced to the point where genetic results can be returned within weeks, meaning that therapeutically actionable variants associated with specific diseases could be developed immediately after diagnosis. Here, we describe 81 probands with a neurodevelopmental disorder (NDD) and family matched controls with full genotype/phenotype information and biobanked stem cells, most of which are consented for sharing. We outline a rapid and scalable pipeline for induced pluripotent stem cell (iPSC) generation directly from clinical collection, without the need for peripheral blood mononuclear cell (PBMC) storage, paired with induction to neurons. We provide a proof of principle for rapid creation of oligonucleotide therapeutics for Kleefstra syndrome. This work introduces a cohort of individuals with NDDs and an implemental pipeline to integrate IG with clinical diagnostics for NDDs. This information documents our experience and provides useful details for clinical centers interested in integrating IG for NDDs with diagnostic sequencing.