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Article

Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings

1
Department of Medical Genetics, University of British Columbia (UBC), Vancouver, BC V6H 3N1, Canada
2
BC Children’s Hospital, Vancouver, BC V5Z 4H4, Canada
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Department of Pediatrics, University of British Columbia (UBC), Vancouver, BC V6T 1Z7, Canada
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The Centre for Applied Genomics and McLaughlin Centre, Hospital for Sick Children and University of Toronto, Toronto, ON M5G 0A4, Canada
5
BC Children’s and Women’s Health Center, Vancouver, BC V6H 3N1, Canada
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Michael Smith Genome Sciences Centre, Vancouver, BC V5Z 4S6, Canada
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Department of Pathology and Laboratory Medicine, University of British Columbia (UBC), Vancouver, BC V6T 1Z7, Canada
*
Author to whom correspondence should be addressed.
Academic Editor: Andreas G. Chiocchetti
Genes 2021, 12(7), 1053; https://doi.org/10.3390/genes12071053
Received: 29 May 2021 / Revised: 21 June 2021 / Accepted: 7 July 2021 / Published: 8 July 2021
(This article belongs to the Special Issue Genetic and Phenotypic Subtypes of Autism Spectrum Disorder)
Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs. View Full-Text
Keywords: Autism Spectrum Disorder (ASD); whole-genome sequencing (WGS); gene variants; RELN gene; SHANK2 gene; quantitative trait hypothesis; complex genetics Autism Spectrum Disorder (ASD); whole-genome sequencing (WGS); gene variants; RELN gene; SHANK2 gene; quantitative trait hypothesis; complex genetics
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MDPI and ACS Style

Dhaliwal, J.; Qiao, Y.; Calli, K.; Martell, S.; Race, S.; Chijiwa, C.; Glodjo, A.; Jones, S.; Rajcan-Separovic, E.; Scherer, S.W.; Lewis, S. Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings. Genes 2021, 12, 1053. https://doi.org/10.3390/genes12071053

AMA Style

Dhaliwal J, Qiao Y, Calli K, Martell S, Race S, Chijiwa C, Glodjo A, Jones S, Rajcan-Separovic E, Scherer SW, Lewis S. Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings. Genes. 2021; 12(7):1053. https://doi.org/10.3390/genes12071053

Chicago/Turabian Style

Dhaliwal, Jasleen, Ying Qiao, Kristina Calli, Sally Martell, Simone Race, Chieko Chijiwa, Armansa Glodjo, Steven Jones, Evica Rajcan-Separovic, Stephen W. Scherer, and Suzanne Lewis. 2021. "Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings" Genes 12, no. 7: 1053. https://doi.org/10.3390/genes12071053

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