Prevalence of clinically actionable disease variants in exceptionally long-lived families.
Incidental genetic findings
Long lived families
Pathogenic variants
Population studies
Journal
BMC medical genomics
ISSN: 1755-8794
Titre abrégé: BMC Med Genomics
Pays: England
ID NLM: 101319628
Informations de publication
Date de publication:
10 04 2020
10 04 2020
Historique:
received:
18
02
2020
accepted:
27
03
2020
entrez:
11
4
2020
pubmed:
11
4
2020
medline:
11
5
2021
Statut:
epublish
Résumé
Phenotypic expression of pathogenic variants in individuals with no family history of inherited disorders remains unclear. We evaluated the prevalence of pathogenic variants in 25 genes associated with Mendelian-inherited disorders in 3015 participants from 485 families in the Long Life Family Study (LLFS). Boot-strapping and Fisher's exact test were used to determine whether allele frequencies in LLFS were significantly different from the allele frequencies reported in publicly available genomic databases. The proportions of pathogenic autosomal dominant mutation carriers in BRCA1 and SDHC in LLFS study participants were similar to those reported in publicly available genomic databases (0.03% vs. 0.0008%, p = 1 for BRCA1, and 0.08% vs. 0.003%, p = 0.05 for SDHC). The frequency of carriers of pathogenic autosomal recessive variants in CPT2, ACADM, SUMF1, WRN, ATM, and ACADVL were also similar in LLFS as compared to those reported in genomic databases. The lack of clinical disease among LLFS participants with well-established pathogenic variants in BRCA1 and SDHC suggests that penetrance of pathogenic variants may be different in long lived families. Further research is needed to better understand the penetrance of pathogenic variants before expanding large scale genomic testing to asymptomatic individuals.
Sections du résumé
BACKGROUND
Phenotypic expression of pathogenic variants in individuals with no family history of inherited disorders remains unclear.
METHODS
We evaluated the prevalence of pathogenic variants in 25 genes associated with Mendelian-inherited disorders in 3015 participants from 485 families in the Long Life Family Study (LLFS). Boot-strapping and Fisher's exact test were used to determine whether allele frequencies in LLFS were significantly different from the allele frequencies reported in publicly available genomic databases.
RESULTS
The proportions of pathogenic autosomal dominant mutation carriers in BRCA1 and SDHC in LLFS study participants were similar to those reported in publicly available genomic databases (0.03% vs. 0.0008%, p = 1 for BRCA1, and 0.08% vs. 0.003%, p = 0.05 for SDHC). The frequency of carriers of pathogenic autosomal recessive variants in CPT2, ACADM, SUMF1, WRN, ATM, and ACADVL were also similar in LLFS as compared to those reported in genomic databases. The lack of clinical disease among LLFS participants with well-established pathogenic variants in BRCA1 and SDHC suggests that penetrance of pathogenic variants may be different in long lived families.
CONCLUSION
Further research is needed to better understand the penetrance of pathogenic variants before expanding large scale genomic testing to asymptomatic individuals.
Identifiants
pubmed: 32272925
doi: 10.1186/s12920-020-0710-5
pii: 10.1186/s12920-020-0710-5
pmc: PMC7146901
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
61Subventions
Organisme : NIA NIH HHS
ID : U01 AG023712
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG023749
Pays : United States
Organisme : NIA NIH HHS
ID : U19 AG063893
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG023746
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG023744
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG023755
Pays : United States
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