Abstract
Background: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions: Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.
Original language | English (US) |
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Article number | 90 |
Journal | Genome Medicine |
Volume | 13 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2021 |
Funding
This work was funded in part by Werner Otto Stiftung (to D.L and H-J.K) and Deutsche Forschungsgemeinschaft (LE4223/1-1 to D.L.; Kr1321/9-1 to H-J.K), by startup funds from University of Alabama, Birmingham (to N.C.Y), by NIH U54 OD030167 (to J.P.M.), by the UCLA Pathology Translational Research Fund (to J.B.M. and F.Q-R.) and by the UCLA California Center for Rare Diseases (to S.F.N). Open Access funding enabled and organized by Projekt DEAL. We thank all affected individuals and their family members/legal guardians. for their participation and collaboration, Hans-Hinrich H?nck (Institute for Human Genetics, UKE Hamburg) for technical assistance, and UKE microscopic imaging facility (umif) for providing assistance with confocal microscopes.
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Genetics(clinical)
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Additional file 2 of Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders
Mannucci, I. (Creator), Dang, N. D. P. (Creator), Huber, H. (Creator), Murry, J. B. (Creator), Abramson, J. (Creator), Althoff, T. (Creator), Banka, S. (Creator), Baynam, G. (Creator), Bearden, D. (Creator), Beleza-Meireles, A. (Creator), Benke, P. J. (Creator), Berland, S. (Creator), Bierhals, T. (Creator), Bilan, F. (Creator), Bindoff, L. A. (Creator), Braathen, G. J. (Creator), Busk, Ø. L. (Creator), Chenbhanich, J. (Creator), Denecke, J. (Creator), Escobar, L. F. (Creator), Estes, C. (Creator), Fleischer, J. (Creator), Groepper, D. (Creator), Haaxma, C. A. (Creator), Hempel, M. (Creator), Holler-Managan, Y. (Creator), Houge, G. (Creator), Jackson, A. (Creator), Kellogg, L. (Creator), Keren, B. (Creator), Kiraly-Borri, C. (Creator), Kraus, C. (Creator), Kubisch, C. (Creator), Le Guyader, G. (Creator), Ljungblad, U. W. (Creator), Brenman, L. M. (Creator), Martinez-Agosto, J. A. (Creator), Might, M. (Creator), Miller, D. T. (Creator), Minks, K. Q. (Creator), Moghaddam, B. (Creator), Nava, C. (Creator), Nelson, S. F. (Creator), Parant, J. M. (Creator), Prescott, T. (Creator), Rajabi, F. (Creator), Randrianaivo, H. (Creator), Reiter, S. F. (Creator), Schuurs-Hoeijmakers, J. (Creator), Shieh, P. B. (Creator), Slavotinek, A. (Creator), Smithson, S. (Creator), Stegmann, A. P. A. (Creator), Tomczak, K. (Creator), Tveten, K. (Creator), Wang, J. (Creator), Whitlock, J. H. (Creator), Zweier, C. (Creator), McWalter, K. (Creator), Juusola, J. (Creator), Quintero-Rivera, F. (Creator), Fischer, U. (Creator), Yeo, N. C. (Creator), Kreienkamp, H.-J. (Creator) & Lessel, D. (Creator), figshare, 2021
DOI: 10.6084/m9.figshare.14643203, https://springernature.figshare.com/articles/dataset/Additional_file_2_of_Genotype_phenotype_correlations_and_novel_molecular_insights_into_the_DHX30-associated_neurodevelopmental_disorders/14643203
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