Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders
Posted on 2021-05-22 - 03:40
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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Mannucci, Ilaria; Dang, Nghi D. P.; Huber, Hannes; Murry, Jaclyn B.; Abramson, Jeff; Althoff, Thorsten; et al. (2021). Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.5434178.v1
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AUTHORS (65)
IM
Ilaria Mannucci
ND
Nghi D. P. Dang
HH
Hannes Huber
JM
Jaclyn B. Murry
JA
Jeff Abramson
TA
Thorsten Althoff
SB
Siddharth Banka
GB
Gareth Baynam
DB
David Bearden
AB
Ana Beleza-Meireles
PB
Paul J. Benke
SB
Siren Berland
TB
Tatjana Bierhals
FB
Frederic Bilan
LB
Laurence A. Bindoff
GB
Geir Julius Braathen
ØB
Øyvind L. Busk
JC
Jirat Chenbhanich
JD
Jonas Denecke
LE
Luis F. Escobar
CATEGORIES
KEYWORDS
ATP-dependent RNA helicaseFacebook-based family support groupHCM missense variantsindividual293Thelicase core motifsnovel Mendelian disordersDHX 30-associated neurodevelopmenta...DHX 30 loss-of-function variants causehelicase activityHEKSG formationmosaic HCM missense variantdhx 30-deficient zebrafishnovel missense variantsCRISPR