De novoand inherited variants inDDX39Bcause a Novel Syndrome Characterized by Neurodevelopmental Delay, Short Stature, and Congenital Hypotonia

Abstract

AbstractDDX39Bis a member of the DEAD-box family of ATP-dependent RNA helicases. DEAD-box proteins are ubiquitously expressed from yeast to humans and perform essential functions associated with mRNA metabolism.DDX39Bis also a crucial component of the TRanscription-EXport (TREX) super protein complex, which recent studies have highlighted the important role of its subunits in neurodevelopmental disorders. Here, we describe six individuals from five families, four with novelde novomissense variants inDDX39B,and one carrying an inherited splicing variant, all presenting with mild to severe global developmental delay, congenital hypotonia, epilepsy, short stature, skeletal abnormalities and variable dysmorphic features. 3D molecular modeling predicts these variants would alter protein structure.DDX39Bis a conserved gene andDrosophila melanogaster(fruit flies) studies were conducted. We generated a new Hel25E Kozak-GAL4 allele which disrupts the fly gene and allows expression of transgenes. We also generated transgenicDDX39B-reference and variant flies. However, human referenceDDX39Bwhen overexpressed ubiquitously leads to lethality but the variants found in the patients do not recapitulate the lethality suggesting that the mutants are loss of function alleles. Blood transcriptomics revealed a significant excess of aberrant splicing events, indicating a disrupted mRNA processing as anticipated from the role ofDDX39Bin mRNA metabolism. Our human genetic data, coupled within silicoandin vivodata supports thatDDX39Bis a novel candidate gene in a potential group of disorders named TREX-complex-related neurodevelopmental syndrome.