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

Autor:	Mannucci I; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany., Dang NDP; Department of Pharmacology and Toxicology, University of Alabama, Birmingham, USA., Huber H; Department of Biochemistry, Theodor Boveri Institute, Biocenter of the University of Würzburg, 97070, Würzburg, Germany., Murry JB; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.; UCLA Clinical Genomics Center, University of California Los Angeles, Los Angeles, CA, USA., Abramson J; Department of Physiology, University of California Los Angeles, Los Angeles, CA, USA., Althoff T; Department of Physiology, University of California Los Angeles, Los Angeles, CA, USA., Banka S; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.; Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Baynam G; Faculty of Medicine and Health Sciences, University of Western Australia, Perth, WA, Australia.; Western Australian Register of Developmental Anomalies, King Edward Memorial Hospital, Perth, Australia.; Telethon Kids Institute, Perth, Australia., Bearden D; Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, Rochester, NY, USA., Beleza-Meireles A; Clinical Genetics Department, University Hospitals Bristol and Weston, Bristol, UK., Benke PJ; Joe DiMaggio Children's Hospital, Hollywood, FL, USA., Berland S; Department of Medical Genetics, Haukeland University Hospital, 5021, Bergen, Norway., Bierhals T; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany., Bilan F; Department of Medical Genetics, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.; Laboratoire de Neurosciences Cliniques et Expérimentales-INSERM U1084, Université de Poitiers, Poitiers, France., Bindoff LA; Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway.; Department of Neurology, Haukeland University Hospital, Bergen, Norway., Braathen GJ; Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway., Busk ØL; Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway., Chenbhanich J; Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA., Denecke J; Department of Pediatrics, University Medical Center Eppendorf, 20246, Hamburg, Germany., Escobar LF; Peyton Manning Children's Hospital, Ascension Health, Indianapolis, IN, USA., Estes C; Peyton Manning Children's Hospital, Ascension Health, Indianapolis, IN, USA., Fleischer J; Department of Pediatrics, Southern Illinois University School of Medicine, Springfield, IL, 62702, USA., Groepper D; Department of Pediatrics, Southern Illinois University School of Medicine, Springfield, IL, 62702, USA., Haaxma CA; Department of Pediatric Neurology, Amalia Children's Hospital and Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands., Hempel M; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany., Holler-Managan Y; Division of Neurology, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Houge G; Department of Medical Genetics, Haukeland University Hospital, 5021, Bergen, Norway., Jackson A; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.; Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Kellogg L; Kaiser Permanente Sacramento, Sacramento, USA., Keren B; Département de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France., Kiraly-Borri C; Genetic Services of Western Australia, Perth, Western Australia, 6008, Australia., Kraus C; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany., Kubisch C; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany., Le Guyader G; Department of Medical Genetics, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.; Laboratoire de Neurosciences Cliniques et Expérimentales-INSERM U1084, Université de Poitiers, Poitiers, France., Ljungblad UW; Department of Pediatrics, Vestfold Hospital, 3116, Tønsberg, Norway., Brenman LM; Department of Genetics, Kaiser Permanente Northern California, Oakland, USA., Martinez-Agosto JA; UCLA Clinical Genomics Center, University of California Los Angeles, Los Angeles, CA, USA.; Semel Institute of Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.; Department of Pediatrics, Division of Medical Genetics at David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.; Department of Human Genetics at David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, USA., Might M; Department of Medicine, Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, 510 20th St S, Birmingham, AL, 35210, USA., Miller DT; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA., Minks KQ; Division of Child Neurology, Department of Neurology, University of Rochester School of Medicine, Rochester, NY, USA., Moghaddam B; Kaiser Permanente Sacramento, Sacramento, USA., Nava C; Département de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France., Nelson SF; UCLA Clinical Genomics Center, University of California Los Angeles, Los Angeles, CA, USA.; Department of Human Genetics at David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, USA.; Center for Duchenne Muscular Dystrophy, University of California Los Angeles, Los Angeles, CA, USA., Parant JM; Department of Pharmacology and Toxicology, University of Alabama, Birmingham, USA., Prescott T; Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway., Rajabi F; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA., Randrianaivo H; UF de Génétique Médicale, GHSR, CHU de La Réunion, Saint Pierre, La Réunion, France., Reiter SF; Department of Medical Genetics, Haukeland University Hospital, 5021, Bergen, Norway., Schuurs-Hoeijmakers J; Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands., Shieh PB; Department of Neurology at David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Slavotinek A; Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA., Smithson S; Clinical Genetics Department, University Hospitals Bristol and Weston, Bristol, UK., Stegmann APA; Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands., Tomczak K; Department of Neurology, Boston Children's Hospital, Boston, MA, USA., Tveten K; Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway., Wang J; Department of Pharmacology and Toxicology, University of Alabama, Birmingham, USA., Whitlock JH; Department of Medicine, Hugh Kaul Precision Medicine Institute, University of Alabama at Birmingham, 510 20th St S, Birmingham, AL, 35210, USA., Zweier C; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, 3010, Bern, Switzerland., McWalter K; GeneDx, Gaithersburg, MD, 20877, USA., Juusola J; GeneDx, Gaithersburg, MD, 20877, USA., Quintero-Rivera F; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.; UCLA Clinical Genomics Center, University of California Los Angeles, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA., Fischer U; Department of Biochemistry, Theodor Boveri Institute, Biocenter of the University of Würzburg, 97070, Würzburg, Germany., Yeo NC; Department of Pharmacology and Toxicology, University of Alabama, Birmingham, USA. nyeo@uab.edu., Kreienkamp HJ; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. kreienkamp@uke.de., Lessel D; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. d.lessel@uke.de.
Jazyk:	angličtina
Zdroj:	Genome medicine [Genome Med] 2021 May 21; Vol. 13 (1), pp. 90. Date of Electronic Publication: 2021 May 21.
DOI:	10.1186/s13073-021-00900-3
Abstrakt:	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.
Databáze:	MEDLINE
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