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

Mannucci I, Dang NDP, Huber H, Murry JB, Abramson J, Althoff T, Banka S, Baynam G, Bearden D, Beleza-Meireles A, Benke PJ, Berland S, Bierhals T, Bilan F, Bindoff LA, Braathen GJ, Busk OL, Chenbhanich J, Denecke J, Escobar LF, Estes C, Fleischer J, Groepper D, Haaxma CA, Hempel M, Holler-Managan Y, Houge G, Jackson A, Kellogg L, Keren B, Kiraly-Borri C, Kraus C, Kubisch C, Le Guyader G, Ljungblad UW, Brenman LM, Martinez-Agosto JA, Might M, Miller DT, Minks KQ, Moghaddam B, Nava C, Nelson SF, Parant JM, Prescott T, Rajabi F, Randrianaivo H, Reiter SF, Schuurs-Hoeijmakers J, Shieh PB, Slavotinek A, Smithson S, Stegmann APA, Tomczak K, Tveten K, Wang J, Whitlock JH, Zweier C, Mcwalter K, Juusola J, Quintero-Rivera F, Fischer U, Yeo NC, Kreienkamp HJ, Lessel D (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 13

Article Number: 90

Journal Issue: 1

DOI: 10.1186/s13073-021-00900-3

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.

Authors with CRIS profile

Involved external institutions

St. Vincent Indianapolis United States (USA) (US) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) University of Alabama at Birmingham (UAB) United States (USA) (US) Julius-Maximilians-Universität Würzburg Germany (DE) University of California Los Angeles (UCLA) United States (USA) (US) Manchester University NHS Foundation Trust (MFT) United Kingdom (GB) University of Western Australia (UWA) Australia (AU) University of Rochester (UR) United States (USA) (US) University Hospitals Bristol NHS Foundation Trust United Kingdom (GB) Joe DiMaggio Children's Hospital United States (USA) (US) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Centre hospitalier universitaire de Poitiers (CHU de Poitiers) France (FR) University of Bergen / Universitetet i Bergen Norway (NO) Telemark Hospital Trust Norway (NO) University of California San Francisco (UCSF) United States (USA) (US) Southern Illinois University Carbondale United States (USA) (US) Radboud University Nijmegen Netherlands (NL) Northwestern University United States (USA) (US) Kaiser Permanente United States (USA) (US) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) Boston Children's Hospital United States (USA) (US) GeneDX United States (USA) (US) Genetic Services of Western Australia (GSWA) Australia (AU) Vestfold Hospital / Sykehuset i Vestfold Norway (NO) Centre Hospitalier Universitaire de La Réunion France (FR)

How to cite

APA:

Mannucci, I., Dang, N.D.P., Huber, H., Murry, J.B., Abramson, J., Althoff, T.,... Lessel, D. (2021). Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders. Genome Medicine, 13(1). https://doi.org/10.1186/s13073-021-00900-3

MLA:

Mannucci, Ilaria, et al. "Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders." Genome Medicine 13.1 (2021).

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