Submission
| Title: |
De novo Missense Variants in DDX39B Cause a Novel Syndrome Characterized by Neurodevelopmental Delay, Short Stature and Congenital Hypotonia |
| Authors: |
Vetrini, Francesco, Department of Medical and Molecular Genetics; Undiagnosed Rare Disease Clinic, Indiana University School of Medicine; Treat K., Department of Medical and Molecular Genetics; Undiagnosed Rare Disease Clinic, Indiana University School of Medicine; White K., Indiana University School of Medicine; Christensen C., Riley Developmental Pediatrics, Riley Children’s Hospital; Sharayu Jangam, Department of Molecular and Human Genetics, Center for Precision Medicine Modeling, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital; Yamamoto S., Department of Molecular and Human Genetics, Center for Precision Medicine Modeling, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital; Kristy Jay, Department of Molecular and Human Genetics, Center for Precision Medicine Modeling, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital; Oguz Kanca, Department of Molecular and Human Genetics, Center for Precision Medicine Modeling, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital; Lynch S.A., Out Lady’s Children’s Hospital Crumlin; Chung, H.Y., Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong; Yuen, L.Y.P., Department of Pathology, Hong Kong Children’s Hospital; Mandy HY Tsang, Department of Paediatrics & Adolescent Medicine, HK, The University of Hong Kong, Department of Clinical Genetics Service Unit, Hong Kong Children’s Hospital; MC Cui, Martin MC Chui – Department of Paediatrics & Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong; Batista J, Julia Baptista University of Plymouth, UK; Bellen, H.J., Department of Molecular and Human Genetics, Center for Precision Medicine Modeling, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital; Wangler, M.F., Department of Molecular and Human Genetics, Center for Precision Medicine Modeling, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital; Conboy, E., Department of Medical and Molecular Genetics; Undiagnosed Rare Disease Clinic, Indiana University School of Medicine |
Abstract
Background/Significance/Rationale: DDX39B is a member of the highly evolutionary conserved DEAD-box family of ATP-dependent RNA helicases, involved in pre-mRNA splicing assembly, nuclear export, and transcriptional regulation. Recent studies have highlighted the important role of DEAD/H-box helicases in both dominant or recessively inherited neurodevelopmental disorders. However, the clinical consequences of disruption of DDX39B function are largely uncharacterized. Here we describe three unrelated cases with novel de novo missense variants in DDX39B, resulting from a GeneMatcher collaboration. Our data suggest that DDX39B is a novel candidate gene associated with a new syndrome characterized by global developmental delay, hypotonia, short stature, and variable neurological presentation.
Methods: We enrolled a patient to Undiagnosed Rare Disease Clinic (URDC) at IUSM presenting with global delay, hypotonia, microcephaly, seizures and autism. Whole Exome Sequencing analysis revealed a de novo c.109G>T p.(Gly37Cys) change in DDX39B. Through Gene Matcher Exchange, two additional patients with overlapping features, were identified carrying de novo missense changes c.257G>A p.(Gly92Asp) and c.368G>A p.(Arg123Gln) in DDX39B. In order to characterize the impact of the mutations, we performed both in silico and in vivo studies in Drosophila model organism.
Results/Findings: All the mutations are absent from population allele frequency databases including the gnomAD and ExAC, affect evolutionarily conserved residues, and are predicted to be pathogenic by different in silico prediction tools. Generation of transgenic flies that allow expression of reference DDX39B (DDX39B-ref) or three variant forms (DDX39B-p.Gly37Cys, -p.Gly92Asp and -p.Arg123Gln) show that these three variants behave as strong or partial loss of function alleles, supporting pathogenicity.
Conclusions/Discussion: Our data suggest that DDX39B, is a novel candidate gene associated with a new syndrome characterized by global developmental delay, hypotonia, short stature, and variable neurological presentation
Translational/Human Health Impact: These findings further expand our understanding of genetic contributions of DEAD-box RNA helicases to neurodevelopmental syndromes and will provide both diagnostics and therapeutic benefits to patients.
