Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings
| Autor: | Sally Martell, Ying Qiao, Evica Rajcan-Separovic, Kristina Calli, Simone Race, Stephen W. Scherer, Jasleen Dhaliwal, Armansa Glodjo, Steven J.M. Jones, Chieko Chijiwa, Suzanne M E Lewis |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male RELN gene Adolescent Autism Spectrum Disorder complex genetics Nerve Tissue Proteins Quantitative trait locus Biology QH426-470 Compound heterozygosity whole-genome sequencing (WGS) gene variants Article Synapse NAV1.8 Voltage-Gated Sodium Channel 03 medical and health sciences Autism Spectrum Disorder (ASD) 0302 clinical medicine Neurodevelopmental disorder mental disorders medicine Genetics Humans Genetic Predisposition to Disease SHANK2 gene Child Gene Genetics (clinical) Whole Genome Sequencing Siblings medicine.disease quantitative trait hypothesis Chromatin SHANK2 DNA-Binding Proteins 030104 developmental biology Autism spectrum disorder Female 030217 neurology & neurosurgery |
| Zdroj: | Genes, Vol 12, Iss 1053, p 1053 (2021) Genes Volume 12 Issue 7 |
| ISSN: | 2073-4425 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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