Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders - Sorbonne Université Access content directly
Journal Articles Genome Medicine Year : 2021

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

Ilaria Mannucci
  • Function : Author
Nghi D P Dang
  • Function : Author
Hannes Huber
  • Function : Author
Jaclyn B Murry
  • Function : Author
Jeff Abramson
  • Function : Author
Thorsten Althoff
  • Function : Author
Siddharth Banka
  • Function : Author
Gareth Baynam
  • Function : Author
David Bearden
  • Function : Author
Ana Beleza-Meireles
  • Function : Author
Paul J Benke
  • Function : Author
Siren Berland
  • Function : Author
Tatjana Bierhals
  • Function : Author
Laurence A Bindoff
  • Function : Author
Geir Julius Braathen
  • Function : Author
Øyvind L Busk
  • Function : Author
Jirat Chenbhanich
  • Function : Author
Jonas Denecke
  • Function : Author
Luis F Escobar
  • Function : Author
Caroline Estes
  • Function : Author
Julie Fleischer
  • Function : Author
Daniel Groepper
  • Function : Author
Charlotte A Haaxma
  • Function : Author
Maja Hempel
  • Function : Author
Yolanda Holler-Managan
  • Function : Author
Gunnar Houge
  • Function : Author
Adam Jackson
  • Function : Author
Laura Kellogg
  • Function : Author
Catherine Kiraly-Borri
  • Function : Author
Cornelia Kraus
  • Function : Author
Christian Kubisch
  • Function : Author
Gwenael Le Guyader
  • Function : Author
Ulf W Ljungblad
  • Function : Author
Leslie Manace Brenman
  • Function : Author
Julian A Martinez-Agosto
  • Function : Author
Matthew Might
  • Function : Author
David T Miller
  • Function : Author
Kelly Q Minks
  • Function : Author
Billur Moghaddam
  • Function : Author
Stanley F Nelson
  • Function : Author
John M Parant
  • Function : Author
Trine Prescott
  • Function : Author
Farrah Rajabi
  • Function : Author
Simone F Reiter
  • Function : Author
Janneke Schuurs-Hoeijmakers
  • Function : Author
Perry B Shieh
  • Function : Author
Anne Slavotinek
  • Function : Author
Sarah Smithson
  • Function : Author
Alexander P A Stegmann
  • Function : Author
Kinga Tomczak
  • Function : Author
Kristian Tveten
  • Function : Author
Jun Wang
  • Function : Author
Jordan H Whitlock
  • Function : Author
Christiane Zweier
  • Function : Author
Kirsty Mcwalter
  • Function : Author
Jane Juusola
  • Function : Author
Fabiola Quintero-Rivera
  • Function : Author
Utz Fischer
  • Function : Author

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.
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Dates and versions

hal-04538727 , version 1 (09-04-2024)

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Ilaria Mannucci, Nghi D P Dang, Hannes Huber, Jaclyn B Murry, Jeff Abramson, et al.. Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders. Genome Medicine, 2021, 13, ⟨10.1186/s13073-021-00900-3⟩. ⟨hal-04538727⟩
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