Community data-driven approach to identify pathogenic founder variants for pan-ethnic carrier screening panels.
ACMG
Carrier screening
Community data-driven approach
Genomics
Pan-ethnic
Pathogenic founder variants
Journal
Human genomics
ISSN: 1479-7364
Titre abrégé: Hum Genomics
Pays: England
ID NLM: 101202210
Informations de publication
Date de publication:
28 03 2023
28 03 2023
Historique:
received:
21
08
2022
accepted:
15
03
2023
medline:
30
3
2023
entrez:
28
3
2023
pubmed:
29
3
2023
Statut:
epublish
Résumé
The American College of Medical Genetics and Genomics (ACMG) recently published new tier-based carrier screening recommendations. While many pan-ethnic genetic disorders are well established, some genes carry pathogenic founder variants (PFVs) that are unique to specific ethnic groups. We aimed to demonstrate a community data-driven approach to creating a pan-ethnic carrier screening panel that meets the ACMG recommendations. Exome sequencing data from 3061 Israeli individuals were analyzed. Machine learning determined ancestries. Frequencies of candidate pathogenic/likely pathogenic (P/LP) variants based on ClinVar and Franklin were calculated for each subpopulation based on the Franklin community platform and compared with existing screening panels. Candidate PFVs were manually curated through community members and the literature. The samples were automatically assigned to 13 ancestries. The largest number of samples was classified as Ashkenazi Jewish (n = 1011), followed by Muslim Arabs (n = 613). We detected one tier-2 and seven tier-3 variants that were not included in existing carrier screening panels for Ashkenazi Jewish or Muslim Arab ancestries. Five of these P/LP variants were supported by evidence from the Franklin community. Twenty additional variants were detected that are potentially pathogenic tier-2 or tier-3. The community data-driven and sharing approaches facilitate generating inclusive and equitable ethnically based carrier screening panels. This approach identified new PFVs missing from currently available panels and highlighted variants that may require reclassification.
Sections du résumé
BACKGROUND
The American College of Medical Genetics and Genomics (ACMG) recently published new tier-based carrier screening recommendations. While many pan-ethnic genetic disorders are well established, some genes carry pathogenic founder variants (PFVs) that are unique to specific ethnic groups. We aimed to demonstrate a community data-driven approach to creating a pan-ethnic carrier screening panel that meets the ACMG recommendations.
METHODS
Exome sequencing data from 3061 Israeli individuals were analyzed. Machine learning determined ancestries. Frequencies of candidate pathogenic/likely pathogenic (P/LP) variants based on ClinVar and Franklin were calculated for each subpopulation based on the Franklin community platform and compared with existing screening panels. Candidate PFVs were manually curated through community members and the literature.
RESULTS
The samples were automatically assigned to 13 ancestries. The largest number of samples was classified as Ashkenazi Jewish (n = 1011), followed by Muslim Arabs (n = 613). We detected one tier-2 and seven tier-3 variants that were not included in existing carrier screening panels for Ashkenazi Jewish or Muslim Arab ancestries. Five of these P/LP variants were supported by evidence from the Franklin community. Twenty additional variants were detected that are potentially pathogenic tier-2 or tier-3.
CONCLUSIONS
The community data-driven and sharing approaches facilitate generating inclusive and equitable ethnically based carrier screening panels. This approach identified new PFVs missing from currently available panels and highlighted variants that may require reclassification.
Identifiants
pubmed: 36978159
doi: 10.1186/s40246-023-00472-w
pii: 10.1186/s40246-023-00472-w
pmc: PMC10044388
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
30Informations de copyright
© 2023. The Author(s).
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