1. Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders
- Author
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Mannucci, I., Dang, N.D.P., Huber, H, Murry, J.B., Abramson, J., Althoff, T., Banka, S., Baynam, G., Bearden, D., Beleza-Meireles, A., Benke, P.J., Berland, S., Bierhals, T., Bilan, F., Bindoff, Laurence, Braathen, G.J., Busk, O.L., Chenbhanich, J., Denecke, J., Escobar, L.F., Estes, C., Fleischer, J., Groepper, D., Haaxma, C.A., Hempel, M., Holler-Managan, Y., Houge, G., Jackson, A., Kellogg, L., Keren, B., Kiraly-Borri, C., Kraus, C., Kubisch, C., Guyader, G. Le, Ljungblad, U.W., Brenman, L.M., Martinez-Agosto, J.A., Might, M., Miller, D.T., Minks, K.Q., Moghaddam, B., Nava, C., Nelson, S.F., Parant, J.M., Prescott, T., Rajabi, F., Randrianaivo, H., Reiter, S.F., Schuurs-Hoeijmakers, J.H.M., Shieh, P.B., Slavotinek, A., Smithson, S., Stegmann, A.P.A., Tomczak, K., Tveten, K., Wang, J, Whitlock, J.H., Zweier, C., McWalter, K., Juusola, J., Quintero-Rivera, F., Fischer, U., Yeo, N.C., Kreienkamp, H.J., Lessel, D., Mannucci, I., Dang, N.D.P., Huber, H, Murry, J.B., Abramson, J., Althoff, T., Banka, S., Baynam, G., Bearden, D., Beleza-Meireles, A., Benke, P.J., Berland, S., Bierhals, T., Bilan, F., Bindoff, Laurence, Braathen, G.J., Busk, O.L., Chenbhanich, J., Denecke, J., Escobar, L.F., Estes, C., Fleischer, J., Groepper, D., Haaxma, C.A., Hempel, M., Holler-Managan, Y., Houge, G., Jackson, A., Kellogg, L., Keren, B., Kiraly-Borri, C., Kraus, C., Kubisch, C., Guyader, G. Le, Ljungblad, U.W., Brenman, L.M., Martinez-Agosto, J.A., Might, M., Miller, D.T., Minks, K.Q., Moghaddam, B., Nava, C., Nelson, S.F., Parant, J.M., Prescott, T., Rajabi, F., Randrianaivo, H., Reiter, S.F., Schuurs-Hoeijmakers, J.H.M., Shieh, P.B., Slavotinek, A., Smithson, S., Stegmann, A.P.A., Tomczak, K., Tveten, K., Wang, J, Whitlock, J.H., Zweier, C., McWalter, K., Juusola, J., Quintero-Rivera, F., Fischer, U., Yeo, N.C., Kreienkamp, H.J., and Lessel, D.
- Abstract
Contains fulltext : 245060.pdf (Publisher’s version ) (Open Access), 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
- Published
- 2021