Genomic analysis of 116 autism families strengthens known risk genes and highlights promising candidates.
Journal
NPJ genomic medicine
ISSN: 2056-7944
Titre abrégé: NPJ Genom Med
Pays: England
ID NLM: 101685193
Informations de publication
Date de publication:
22 Mar 2024
22 Mar 2024
Historique:
received:
20
10
2023
accepted:
27
02
2024
medline:
23
3
2024
pubmed:
23
3
2024
entrez:
23
3
2024
Statut:
epublish
Résumé
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component in which rare variants contribute significantly to risk. We performed whole genome and/or exome sequencing (WGS and WES) and SNP-array analysis to identify both rare sequence and copy number variants (SNVs and CNVs) in 435 individuals from 116 ASD families. We identified 37 rare potentially damaging de novo SNVs (pdSNVs) in the cases (n = 144). Interestingly, two of them (one stop-gain and one missense variant) occurred in the same gene, BRSK2. Moreover, the identification of 8 severe de novo pdSNVs in genes not previously implicated in ASD (AGPAT3, IRX5, MGAT5B, RAB8B, RAP1A, RASAL2, SLC9A1, YME1L1) highlighted promising candidates. Potentially damaging CNVs (pdCNVs) provided support to the involvement of inherited variants in PHF3, NEGR1, TIAM1 and HOMER1 in neurodevelopmental disorders (NDD), although mostly acting as susceptibility factors with incomplete penetrance. Interpretation of identified pdSNVs/pdCNVs according to the ACMG guidelines led to a molecular diagnosis in 19/144 cases, although this figure represents a lower limit and is expected to increase thanks to further clarification of the role of likely pathogenic variants in ASD/NDD candidate genes not yet established. In conclusion, our study highlights promising ASD candidate genes and contributes to characterize the allelic diversity, mode of inheritance and phenotypic impact of de novo and inherited risk variants in ASD/NDD genes.
Identifiants
pubmed: 38519481
doi: 10.1038/s41525-024-00411-1
pii: 10.1038/s41525-024-00411-1
doi:
Types de publication
Journal Article
Langues
eng
Pagination
21Subventions
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : GR-2013-02357561
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : GR-2013-02357561
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : GR-2013-02357561
Organisme : U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)
ID : 3UM1HG008901
Informations de copyright
© 2024. The Author(s).
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