Genome Sequencing and Comprehensive Rare Variant Analysis of 465 Families with Neurodevelopmental Disorders
Abstract Purpose Despite significant progress in unravelling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis following microarray and/or exome sequencing. Here we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in NDD participants from the NIHR BioResource project.Methods Short-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, complex SVs, or required distal variant phasing.Results Causal variants were identified in 36% affected individuals (177/489) and a further 26% (129/489) had a variant of uncertain significance, after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were SNVs/indels, and the remainder were structural variants (SVs), non-coding, and mitochondrial variants. Furthermore, long-read GS facilitated resolution of challenging SVs and invalidated variants of difficult interpretation from short-read GS.Conclusion This study demonstrates the value of short-read GS, complemented with long-reads, to investigate the genetic causes of NDDs. GS provides a comprehensive and unbiased method to identify all types of variants throughout the nuclear and mitochondrial genome in NDD individuals..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 23. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sanchis-Juan, Alba [VerfasserIn] |
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| doi: |
10.1101/2023.03.01.23285719 |
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| PPN (Katalog-ID): |
XBI038895005 |
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| 520 | |a Abstract Purpose Despite significant progress in unravelling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis following microarray and/or exome sequencing. Here we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in NDD participants from the NIHR BioResource project.Methods Short-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, complex SVs, or required distal variant phasing.Results Causal variants were identified in 36% affected individuals (177/489) and a further 26% (129/489) had a variant of uncertain significance, after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were SNVs/indels, and the remainder were structural variants (SVs), non-coding, and mitochondrial variants. Furthermore, long-read GS facilitated resolution of challenging SVs and invalidated variants of difficult interpretation from short-read GS.Conclusion This study demonstrates the value of short-read GS, complemented with long-reads, to investigate the genetic causes of NDDs. GS provides a comprehensive and unbiased method to identify all types of variants throughout the nuclear and mitochondrial genome in NDD individuals. | ||
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