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[Preprint]. 2023 Dec 27:2023.12.21.23300383.
doi: 10.1101/2023.12.21.23300383.

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

Marcello Scala  1   2 , Clarrisa A Bradley  3   4   5 , Jennifer L Howe  3   4 , Brett Trost  3   4 , Nelson Bautista Salazar  3   4 , Carole Shum  4 , Miriam S Reuter  3   4 , Jeffrey R MacDonald  3   4 , Sangyoon Y Ko  5 , Paul W Frankland  5   6 , Leslie Granger  7 , George Anadiotis  7 , Verdiana Pullano  8 , Alfredo Brusco  9   10 , Roberto Keller  11 , Sarah Parisotto  12 , Helio F Pedro  12 , Laina Lusk  13   14   15 , Pamela Pojomovsky McDonnell  13   14   16 , Ingo Helbig  13   14   15   16 , Sureni V Mullegama  17 ; Undiagnosed Diseases Network; Emilie D Douine  18 , Bianca E Russell  18 , Stanley F Nelson  18 , Federico Zara  1   2 , Stephen W Scherer  3   4   19   20
Affiliations

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

Marcello Scala et al. medRxiv. .

Update in

  • Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus.
    Scala M, Bradley CA, Howe JL, Trost B, Salazar NB, Shum C, Mendes M, Reuter MS, Anagnostou E, MacDonald JR, Ko SY, Frankland PW, Charlebois J, Elsabbagh M, Granger L, Anadiotis G, Pullano V, Brusco A, Keller R, Parisotto S, Pedro HF, Lusk L, McDonnell PP, Helbig I, Mullegama SV; Undiagnosed Diseases Network; Douine ED, Corona RI, Russell BE, Nelson SF, Graziano C, Schwab M, Simone L, Zara F, Scherer SW. Scala M, et al. Am J Hum Genet. 2025 Jan 2;112(1):154-167. doi: 10.1016/j.ajhg.2024.11.003. Epub 2024 Dec 19. Am J Hum Genet. 2025. PMID: 39706195 Free PMC article.

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 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.

Keywords: Autism; Autism spectrum disorder; DDX53; RNA helicase; Xp22.11 locus.

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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. Summary of the genotypic and phenotypic features of the ASD-related Xp22.11 locus.
The Xp22.11 locus includes DDX53 (MIM * 301079), PTCHD1 (MIM * 300828), and the long noncoding RNA (lncRNA) PTCHD1-AS (PTCHD1 Antisense RNA (Head To Head)). A number of deletions identified in ASD participants were found to disrupt exons of the upstream lncRNA PTCHD1-AS and/or the DDX53 gene. a = SFARI Gene with curated EAGLE gene scores: https://gene.sfari.org/; b = ClinGen https://clinicalgenome.org/; c = EAGLE gene curation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10357004.
Figure 2.
Figure 2.. Pedigrees of the reported families and genetic findings in all DDX53 participants.
A) Pedigrees of the six families showing the segregation of the DDX53 variants in affected individuals and the parents. All variants were inherited from unaffected mothers. The carrier status is indicated by small-filled circles. The mosaic status of the mother of the proband #5 is indicated by a small empty circle. B) Schematic representation of the total of the DDX53 variants mapped to the unique protein isoform (NP_874358.2). The variants identified in the described families and those identified in participants from the SFARI and MSSNG databases are reported in blue and black, respectively. DEXDc = DEAD-like Helicases superfamily domain; HELICc = helicase conserved C-terminal domain; KH = K homology domain.
Figure 3.
Figure 3.. Graphic representation of intolerance to DDX53 variants.
Using the Metadome software (https://stuart.radboudumc.nl/metadome/), we mapped the variants identified in our cohort and in the SFARI and MSSNG datasets to the DDX53 protein. Most variants were found to affect amino acid residues that showed intolerance to variation according to their variation in the gnomAD dataset. While some amino acids were rarely impacted by genetic changes, variants in other residues are absent in gnomAD.
Figure 4.
Figure 4.
A) Graphical representation of human, mouse, and rat syntenic regions and breaks in chrX:10,445,310-35,803,753 (GRCh38). Syntenic alignment between human and mouse show inverted orientation of two corresponding segments between human and mouse. Syntenic alignment between human and rat is shown to highlight the mouse-specific inversion of this chromosomal segment, and the shared syntenic break located just upstream of the PTCHD1 gene. B) Inset of human-mouse syntenic region at the PTCHD1-AS locus. C) Full phylogenetic tree of DDX53 and DDX43 (right panel) created by Treefam. Red triangle denotes a duplication event. Green circle denotes a speciation event. Inset of DDX53 orthologs (left panel). D) Phylogenetic tree of DDX53 and DDX43 in common model organisms.
See this image and copyright information in PMC

References

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Web resources
    1. CADD; https://cadd.gs.washington.edu
    1. ClinVar; https://www.ncbi.nlm.nih.gov/clinvar
    1. Combined Annotation Dependent Depletion (CADD); http://cadd.gs.washington.edu
    1. Database of Genomic Variants (DGV); http://dgv.tcag.ca/dgv/app/home
    1. DECIPHER; https://decipher.sanger.ac.uk

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