Abstract

Defining different genetic subtypes of autism spectrum disorder (ASD) can enable the prediction of developmental outcomes. Based on minor physical and major congenital anomalies, we categorize 325 Canadian children with ASD into dysmorphic and nondysmorphic subgroups. We develop a method for calculating a patient-level, genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD have a significantly higher GRVS compared to those with nondysmorphic ASD (P = 0.03). Using the polygenic transmission disequilibrium test, we observe an over-transmission of ASD-associated common variants in nondysmorphic ASD probands (P = 2.9 × 10−3). These findings replicate using WGS data from 442 ASD probands with accompanying morphology data from the Simons Simplex Collection. Our results provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.

Morphological subtypes of autism spectrum disorder (ASD) may differ in their genetic bases. Chan et al. develop a method for calculating a patient-level, genome-wide rare variant score and find significant differences in rare and common variant associations between dysmorphic and nondysmorphic ASD groups.

Details

Title
Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder
Author
Chan, Ada J. S. 1 ; Engchuan, Worrawat 1 ; Reuter, Miriam S. 2   VIAFID ORCID Logo  ; Wang, Zhuozhi 1 ; Thiruvahindrapuram, Bhooma 1   VIAFID ORCID Logo  ; Trost, Brett 1   VIAFID ORCID Logo  ; Nalpathamkalam, Thomas 1 ; Negrijn, Carol 3 ; Lamoureux, Sylvia 1 ; Pellecchia, Giovanna 1   VIAFID ORCID Logo  ; Patel, Rohan V. 1   VIAFID ORCID Logo  ; Sung, Wilson W. L. 1   VIAFID ORCID Logo  ; MacDonald, Jeffrey R. 1   VIAFID ORCID Logo  ; Howe, Jennifer L. 1 ; Vorstman, Jacob 4   VIAFID ORCID Logo  ; Sondheimer, Neal 5   VIAFID ORCID Logo  ; Takahashi, Nicole 6 ; Miles, Judith H. 6 ; Anagnostou, Evdokia 7 ; Tammimies, Kristiina 8   VIAFID ORCID Logo  ; Zarrei, Mehdi 1 ; Merico, Daniele 9   VIAFID ORCID Logo  ; Stavropoulos, Dimitri J. 10 ; Yuen, Ryan K. C. 11   VIAFID ORCID Logo  ; Fernandez, Bridget A. 12   VIAFID ORCID Logo  ; Scherer, Stephen W. 13   VIAFID ORCID Logo 

1  The Hospital for Sick Children, The Centre for Applied Genomics, Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); The Hospital for Sick Children, Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646) 
2  The Hospital for Sick Children, The Centre for Applied Genomics, Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); The Hospital for Sick Children, Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); The Hospital for Sick Children, CGEn, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646) 
3  Eastern Health, Provincial Medical Genetics Program, St. John’s, Canada (GRID:grid.42327.30) 
4  The Hospital for Sick Children, The Centre for Applied Genomics, Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); The Hospital for Sick Children, Department of Psychiatry, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); University of Toronto, Department of Psychiatry, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
5  University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); The Hospital for Sick Children, Division of Clinical and Metabolic Genetics, Department of Pediatrics, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); University of Toronto, Department of Pediatrics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
6  University of Missouri, Thompson Center for Autism and Neurodevelopmental Disorders, Columbia, USA (GRID:grid.134936.a) (ISNI:0000 0001 2162 3504) 
7  University of Toronto, Department of Pediatrics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); Holland Bloorview Kids Rehabilitation Hospital, Toronto, Canada (GRID:grid.414294.e) (ISNI:0000 0004 0572 4702) 
8  Karolinska Institutet, Department of Women’s and Children’s Health, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
9  The Hospital for Sick Children, The Centre for Applied Genomics, Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); Deep Genomics Inc., Toronto, Canada (GRID:grid.42327.30) 
10  The Hospital for Sick Children, Department of Paediatric Laboratory Medicine, Genome Diagnostics, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
11  The Hospital for Sick Children, The Centre for Applied Genomics, Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); The Hospital for Sick Children, Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
12  Eastern Health, Provincial Medical Genetics Program, St. John’s, Canada (GRID:grid.17063.33); Children’s Hospital Los Angeles, Keck School of Medicine of University of Southern California, Department of Pediatrics and The Saban Research Institute, Los Angeles, USA (GRID:grid.239546.f) (ISNI:0000 0001 2153 6013); Memorial University of Newfoundland, Discipline of Genetics, Faculty of Medicine, St. John’s, Canada (GRID:grid.25055.37) (ISNI:0000 0000 9130 6822) 
13  The Hospital for Sick Children, The Centre for Applied Genomics, Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); The Hospital for Sick Children, Genetics and Genome Biology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, McLaughlin Centre, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-34112-z
ProQuest document ID
2729999784
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.