Work

P588: De novo and inherited variants in DDX39B cause a novel neurodevelopmental syndrome characterized by hypotonia, epilepsy, and short stature

Year: 2024

Type: article

Abstract: DDX39B is 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. DDX39B is 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 novel de novo missense variants in DDX39B, 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. DDX39B is a conserved gene and Drosophila 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 transgenic DDX39B -reference and variant flies. However, human reference DDX39B when 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 of DDX39B in mRNA metabolism. Our human genetic data, coupled with in silico and in vivo data supports that DDX39B is a novel candidate gene in a potential group of disorders named TREX-complex-related neurodevelopmental syndrome.

Source: Genetics in Medicine Open

DOI: 10.1016/j.gimo.2024.101494