Genetic variants in DDX53 contribute to Autism Spectrum Disorder associated with the Xp22.11 locus.

Autor:	Scala M; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.; UOC Genetica Medica, IRCCS Giannina Gaslini, Genoa, Italy., Bradley CA; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Program in Neurosciences and Mental Health, The Hospital for Sick Children and Department of Physiology, University of Toronto, Toronto, Ontario, Canada., Howe JL; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Trost B; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Salazar NB; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Shum C; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Reuter MS; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., MacDonald JR; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Ko SY; Program in Neurosciences and Mental Health, The Hospital for Sick Children and Department of Physiology, University of Toronto, Toronto, Ontario, Canada., Frankland PW; Program in Neurosciences and Mental Health, The Hospital for Sick Children and Department of Physiology, University of Toronto, Toronto, Ontario, Canada.; Department of Psychology and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada., Granger L; Department of Genetics and Metabolism, Randall Children's Hospital, Portland, OR 97227, USA., Anadiotis G; Department of Genetics and Metabolism, Randall Children's Hospital, Portland, OR 97227, USA., Pullano V; Department of Medical Sciences, University of Torino, Torino, Italy., Brusco A; Department of Neurosciences Rita Levi-Montalcini, University of Turin, 10126 Turin, Italy.; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy., Keller R; Adult Autism Centre DSM ASL Città di Torino, 10138 Turin, Italy., Parisotto S; Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, New Jersey, USA., Pedro HF; Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, New Jersey, USA., Lusk L; Epilepsy Neurogenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA, USA., McDonnell PP; Epilepsy Neurogenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Helbig I; Epilepsy Neurogenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Mullegama SV; GeneDx, Gaithersburg, MD, USA., Douine ED; Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA., Russell BE; Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA., Nelson SF; Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA., Zara F; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.; UOC Genetica Medica, IRCCS Giannina Gaslini, Genoa, Italy., Scherer SW; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.; McLaughlin Centre, Toronto, ON M5G 0A4, Canada.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2023 Dec 27. Date of Electronic Publication: 2023 Dec 27.
DOI:	10.1101/2023.12.21.23300383
Abstrakt:	Autism Spectrum Disorder (ASD) exhibits an ~4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1 gene, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ~1Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS . While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been examined, in part because there is no apparent functional murine orthologue. Through clinical testing, here, we identified 6 males and 1 female with ASD from 6 unrelated families carrying rare, predicted-damaging or loss-of-function variants in DDX53 . Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 24 additional individuals with ASD harboring rare, damaging DDX53 variations, including the same variants detected in two families from the original clinical analysis. In this extended cohort of 31 participants with ASD (28 male, 3 female), we identified 25 mostly maternally-inherited variations in DDX53 , including 18 missense changes, 2 truncating variants, 2 in-frame variants, 2 deletions in the 3' UTR and 1 copy number deletion. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mouse, may also influence the design and interpretation of murine-modelling of ASD. Competing Interests: Competing interests At the time of this study and its publication, S.W.S. served on the Scientific Advisory Committee of Population Bio. Intellectual property from aspects of his research held at The Hospital for Sick Children are licensed to Athena Diagnostics and Population Bio. These relationships did not influence data interpretation or presentation during this study but are disclosed for potential future considerations. SVM is an employee of GeneDx, LLC. HFP is on the research advisory boards and speaker bureau for Takeda Pharmaceutical, AvroBio, Amicus Therapeutics, Sanofi, Alexion Therapeutics, Denali Therapeutics and Acer Therapeutics. All other authors declare no conflict of interest.
Databáze:	MEDLINE
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