Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

  1. Mannucci, Ilaria
  2. Dang, Nghi D. P.
  3. Huber, Hannes
  4. Murry, Jaclyn B.
  5. Abramson, Jeff
  6. Althoff, Thorsten
  7. Banka, Siddharth
  8. Baynam, Gareth
  9. Bearden, David
  10. Beleza-Meireles, Ana
  11. Benke, Paul J.
  12. Berland, Siren
  13. Bierhals, Tatjana
  14. Bilan, Frederic
  15. Bindoff, Laurence A.
  16. Braathen, Geir Julius
  17. Busk, Øyvind L.
  18. Chenbhanich, Jirat
  19. Denecke, Jonas
  20. Escobar, Luis F.
  21. Estes, Caroline
  22. Fleischer, Julie
  23. Groepper, Daniel
  24. Haaxma, Charlotte A.
  25. Hempel, Maja
  26. Holler-Managan, Yolanda
  27. Houge, Gunnar
  28. Jackson, Adam
  29. Kellogg, Laura
  30. Keren, Boris
  31. Kiraly-Borri, Catherine
  32. Kraus, Cornelia
  33. Kubisch, Christian
  34. Le Guyader, Gwenael
  35. Ljungblad, Ulf W.
  36. Brenman, Leslie Manace
  37. Martinez-Agosto, Julian A.
  38. Might, Matthew
  39. Miller, David T.
  40. Minks, Kelly Q.
  41. Moghaddam, Billur
  42. Nava, Caroline
  43. Nelson, Stanley F.
  44. Parant, John M.
  45. Prescott, Trine
  46. Rajabi, Farrah
  47. Randrianaivo, Hanitra
  48. Reiter, Simone F.
  49. Schuurs-Hoeijmakers, Janneke
  50. Shieh, Perry B.
  51. Slavotinek, Anne
  52. Smithson, Sarah
  53. Stegmann, Alexander P. A.
  54. Tomczak, Kinga
  55. Tveten, Kristian
  56. Wang, Jun
  57. Whitlock, Jordan H.
  58. Zweier, Christiane
  59. McWalter, Kirsty
  60. Juusola, Jane
  61. Quintero-Rivera, Fabiola
  62. Fischer, Utz
  63. Yeo, Nan Cher
  64. Kreienkamp, Hans-Jürgen
  65. Lessel, Davor ORCID logo

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1000 Titel
  • Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders
1000 Autor/in
  1. Mannucci, Ilaria |
  2. Dang, Nghi D. P. |
  3. Huber, Hannes |
  4. Murry, Jaclyn B. |
  5. Abramson, Jeff |
  6. Althoff, Thorsten |
  7. Banka, Siddharth |
  8. Baynam, Gareth |
  9. Bearden, David |
  10. Beleza-Meireles, Ana |
  11. Benke, Paul J. |
  12. Berland, Siren |
  13. Bierhals, Tatjana |
  14. Bilan, Frederic |
  15. Bindoff, Laurence A. |
  16. Braathen, Geir Julius |
  17. Busk, Øyvind L. |
  18. Chenbhanich, Jirat |
  19. Denecke, Jonas |
  20. Escobar, Luis F. |
  21. Estes, Caroline |
  22. Fleischer, Julie |
  23. Groepper, Daniel |
  24. Haaxma, Charlotte A. |
  25. Hempel, Maja |
  26. Holler-Managan, Yolanda |
  27. Houge, Gunnar |
  28. Jackson, Adam |
  29. Kellogg, Laura |
  30. Keren, Boris |
  31. Kiraly-Borri, Catherine |
  32. Kraus, Cornelia |
  33. Kubisch, Christian |
  34. Le Guyader, Gwenael |
  35. Ljungblad, Ulf W. |
  36. Brenman, Leslie Manace |
  37. Martinez-Agosto, Julian A. |
  38. Might, Matthew |
  39. Miller, David T. |
  40. Minks, Kelly Q. |
  41. Moghaddam, Billur |
  42. Nava, Caroline |
  43. Nelson, Stanley F. |
  44. Parant, John M. |
  45. Prescott, Trine |
  46. Rajabi, Farrah |
  47. Randrianaivo, Hanitra |
  48. Reiter, Simone F. |
  49. Schuurs-Hoeijmakers, Janneke |
  50. Shieh, Perry B. |
  51. Slavotinek, Anne |
  52. Smithson, Sarah |
  53. Stegmann, Alexander P. A. |
  54. Tomczak, Kinga |
  55. Tveten, Kristian |
  56. Wang, Jun |
  57. Whitlock, Jordan H. |
  58. Zweier, Christiane |
  59. McWalter, Kirsty |
  60. Juusola, Jane |
  61. Quintero-Rivera, Fabiola |
  62. Fischer, Utz |
  63. Yeo, Nan Cher |
  64. Kreienkamp, Hans-Jürgen |
  65. Lessel, Davor |
1000 Erscheinungsjahr 2021
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2021-05-21
1000 Erschienen in
1000 Quellenangabe
  • 13(1):90
1000 Copyrightjahr
  • 2021
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1186/s13073-021-00900-3 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140440/ |
1000 Publikationsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • 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.
1000 Sacherschließung
lokal Bioinformatics
lokal Neurodevelopmental Disorders/diagnosis [MeSH]
lokal Gene Expression [MeSH]
lokal RNA Helicases/metabolism [MeSH]
lokal Neurodevelopmental Disorders/genetics [MeSH]
lokal Zebrafish [MeSH]
lokal RNA Helicases/chemistry [MeSH]
lokal Phenotype [MeSH]
lokal Systems Biology
lokal Metabolomics
lokal Human Genetics
lokal Genetic Association Studies/methods [MeSH]
lokal Genetic Predisposition to Disease [MeSH]
lokal Mutation [MeSH]
lokal Humans [MeSH]
lokal Gene Knockdown Techniques [MeSH]
lokal Animals [MeSH]
lokal Immunohistochemistry [MeSH]
lokal RNA Helicases/genetics [MeSH]
lokal Cancer Research
lokal Germ-Line Mutation [MeSH]
lokal Research
lokal HEK293 Cells [MeSH]
lokal Biomarkers [MeSH]
lokal Medicine/Public Health, general
1000 Liste der Beteiligten
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