Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus

Marcello Scala; Clarrisa A Bradley; Jennifer L Howe; Brett Trost; Nelson Bautista Salazar; Carole Shum; Marla Mendes; Miriam S Reuter; Evdokia Anagnostou; Jeffrey R MacDonald; Sangyoon Y Ko; Paul W Frankland; Jessica Charlebois; Mayada Elsabbagh; Leslie Granger; George Anadiotis; Verdiana Pullano; Alfredo Brusco; Roberto Keller; Sarah Parisotto; Helio F Pedro; Laina Lusk; Pamela Pojomovsky McDonnell; Ingo Helbig; Sureni V Mullegama; Undiagnosed Diseases Network; Emilie D Douine; Rosario Ivetth Corona; Bianca E Russell; Stanley F Nelson; Claudio Graziano; Maria Schwab; Laurie Simone; Federico Zara; Stephen W Scherer

doi:10.1016/j.ajhg.2024.11.003

Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus

Am J Hum Genet. 2024 Nov 28:S0002-9297(24)00412-9. doi: 10.1016/j.ajhg.2024.11.003. Online ahead of print.

Authors

Marcello Scala¹, Clarrisa A Bradley², Jennifer L Howe³, Brett Trost³, Nelson Bautista Salazar³, Carole Shum³, Marla Mendes³, Miriam S Reuter³, Evdokia Anagnostou⁴, Jeffrey R MacDonald³, Sangyoon Y Ko², Paul W Frankland⁵, Jessica Charlebois⁶, Mayada Elsabbagh⁶, Leslie Granger⁷, George Anadiotis⁷, Verdiana Pullano⁸, Alfredo Brusco⁹, Roberto Keller¹⁰, Sarah Parisotto¹¹, Helio F Pedro¹¹, Laina Lusk¹², Pamela Pojomovsky McDonnell¹³, Ingo Helbig¹⁴, Sureni V Mullegama¹⁵; Undiagnosed Diseases Network; Emilie D Douine¹⁶, Rosario Ivetth Corona¹⁶, Bianca E Russell¹⁶, Stanley F Nelson¹⁶, Claudio Graziano¹⁷, Maria Schwab¹¹, Laurie Simone¹¹, Federico Zara¹⁸, Stephen W Scherer¹⁹

Affiliations

¹ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genoa, Italy; UOC Genetica Medica, IRCCS Giannina Gaslini, Genoa, Italy. Electronic address: [email protected].
² 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; Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada.
³ 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.
⁴ Department of Pediatrics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Program in Neurosciences and Mental Health, The Hospital for Sick Children and Department of Physiology, University of Toronto, Toronto, ON, Canada.
⁵ Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada; Department of Psychology and Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
⁶ Azrieli Centre for Autism Research, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada.
⁷ Department of Genetics and Metabolism, Randall Children's Hospital, Portland, OR 97227, USA.
⁸ Department of Medical Sciences, University of Torino, Torino, Italy.
⁹ 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.
¹⁰ Adult Autism Centre DSM ASL Città di Torino, 10138 Turin, Italy.
¹¹ Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, NJ, USA.
¹² 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.
¹³ 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.
¹⁴ 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.
¹⁵ GeneDx, Gaithersburg, MD, USA.
¹⁶ Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA.
¹⁷ Dipartimento MeLabeT, AUSL della Romagna, Pievesestina di Cesena, Cesena, Italy.
¹⁸ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genoa, Italy; UOC Genetica Medica, IRCCS Giannina Gaslini, Genoa, Italy.
¹⁹ 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. Electronic address: [email protected].

PMID: 39706195
DOI: 10.1016/j.ajhg.2024.11.003

Abstract

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, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ∼1 Mb), 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 comprehensively examined, in part because there is no apparent functional murine ortholog. Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants in DDX53. Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damaging DDX53 variations, including two variants detected in families from the original clinical analysis. 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 mice, may also influence the design and interpretation of murine modeling of ASD.

Keywords: DDX53; MSSNG; PTCHD1-AS; RNA helicase; SFARI; Xp22.11 locus; autism; autism spectrum disorder; neurodevelopmental disorders; non-coding RNA.