Association between de novo variants of nuclear-encoded mitochondrial-related genes and undiagnosed developmental disorder and autism
© The Author(s) 2023. Published by Oxford University Press on behalf of the Association of Physicians..
BACKGROUND: Evidence suggests that mitochondrial abnormalities increase the risk of two neurodevelopmental disorders: undiagnosed developmental disorder (UDD) and autism spectrum disorder (ASD). However, which nuclear-encoded mitochondrial-related genes (NEMGs) were associated with UDD-ASD is unclear.
AIM: To explore the association between de novo variants (DNVs) of NEMGs and UDD-ASD.
DESIGN: Comprehensive analysis based on DNVs of NEMGs identified in patients (31 058 UDD probands and 10 318 ASD probands) and 4262 controls.
METHODS: By curating NEMGs and cataloging publicly published DNVs in NEMGs, we compared the frequency of DNVs in cases and controls. We also applied a TADA-denovo model to highlight disease-associated NEMGs and characterized them based on gene intolerance, functional networks and expression patterns.
RESULTS: Compared with levels in 4262 controls, an excess of protein-truncating variants and deleterious missense variants in 1421 cataloged NEMGs from 41 376 patients (31 058 UDD and 10 318 ASD probands) was observed. Overall, 3.23% of de novo deleterious missense variants and 3.20% of de novo protein-truncating variants contributed to 1.1% and 0.39% of UDD-ASD cases, respectively. We prioritized 130 disease-associated NEMGs and showed distinct expression patterns in the developing human brain. Disease-associated NEMGs expression was enriched in both excitatory and inhibitory neuronal lineages from the developing human cortex.
CONCLUSIONS: Rare genetic alterations of disease-associated NEMGs may play a role in UDD-ASD development and lay the groundwork for a better understanding of the biology of UDD-ASD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:117 |
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| Enthalten in: |
QJM : monthly journal of the Association of Physicians - 117(2024), 4 vom: 12. Apr., Seite 269-276 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Luo, T [VerfasserIn] |
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| Anmerkungen: |
Date Completed 15.04.2024 Date Revised 25.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/qjmed/hcad249 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM364227044 |
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| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of the Association of Physicians. | ||
| 520 | |a BACKGROUND: Evidence suggests that mitochondrial abnormalities increase the risk of two neurodevelopmental disorders: undiagnosed developmental disorder (UDD) and autism spectrum disorder (ASD). However, which nuclear-encoded mitochondrial-related genes (NEMGs) were associated with UDD-ASD is unclear | ||
| 520 | |a AIM: To explore the association between de novo variants (DNVs) of NEMGs and UDD-ASD | ||
| 520 | |a DESIGN: Comprehensive analysis based on DNVs of NEMGs identified in patients (31 058 UDD probands and 10 318 ASD probands) and 4262 controls | ||
| 520 | |a METHODS: By curating NEMGs and cataloging publicly published DNVs in NEMGs, we compared the frequency of DNVs in cases and controls. We also applied a TADA-denovo model to highlight disease-associated NEMGs and characterized them based on gene intolerance, functional networks and expression patterns | ||
| 520 | |a RESULTS: Compared with levels in 4262 controls, an excess of protein-truncating variants and deleterious missense variants in 1421 cataloged NEMGs from 41 376 patients (31 058 UDD and 10 318 ASD probands) was observed. Overall, 3.23% of de novo deleterious missense variants and 3.20% of de novo protein-truncating variants contributed to 1.1% and 0.39% of UDD-ASD cases, respectively. We prioritized 130 disease-associated NEMGs and showed distinct expression patterns in the developing human brain. Disease-associated NEMGs expression was enriched in both excitatory and inhibitory neuronal lineages from the developing human cortex | ||
| 520 | |a CONCLUSIONS: Rare genetic alterations of disease-associated NEMGs may play a role in UDD-ASD development and lay the groundwork for a better understanding of the biology of UDD-ASD | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Pan, J |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Y |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, X |e verfasserin |4 aut | |
| 700 | 1 | |a Li, K |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, G |e verfasserin |4 aut | |
| 700 | 1 | |a Li, B |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Z |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, K |e verfasserin |4 aut | |
| 700 | 1 | |a Li, J |e verfasserin |4 aut | |
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