Title
Biased pathogenic assertions of loss of function variants challenge molecular diagnosis of admixed individuals
Date Issued
2021
Access level
metadata only access
Resource Type
journal article
Author(s)
Naslavsky M.S.
Scliar M.O.
Nunes K.
Wang J.Y.T.
Yamamoto G.L.
Duarte Y.A.O.
Passos-Bueno M.R.
Meyer D.
Zatz M.
Publisher(s)
John Wiley and Sons Inc
Abstract
Diagnosis of individuals affected by monogenic disorders was significantly improved by next-generation sequencing targeting clinically relevant genes. Whole exomes yield a large number of variants that require several filtering steps, prioritization, and pathogenicity classification. Among the criteria recommended by ACMG, those that rely on population databases critically affect analyses of individuals with underrepresented ancestries. Population-specific allelic frequencies need consideration when characterizing potential deleteriousness of variants. An orthogonal input for classification is annotation of variants previously classified as pathogenic as a criterion that provide supporting evidence widely sourced at ClinVar. We used a whole-genome dataset from a census-based cohort of 1,171 elderly individuals from São Paulo, Brazil, highly admixed, and unaffected by severe monogenic disorders, to investigate if pathogenic assertions in ClinVar are enriched with higher proportions of European ancestry, indicating bias. Potential loss of function (pLOF) variants were filtered from 4,250 genes associated with Mendelian disorders and annotated with ClinVar assertions. Over 1,800 single nucleotide pLOF variants were included, 381 had non-benign assertions. Among carriers (N = 463), average European ancestry was significantly higher than noncarriers (N = 708; p =.011). pLOFs in genomic contexts of non-European local ancestries were nearly three times less likely to have any ClinVar entry (OR = 0.353; p <.0001). Independent pathogenicity assertions are useful for variant classification in molecular diagnosis. However, European overrepresentation of assertions can promote distortions when classifying variants in non-European individuals, even in admixed samples with a relatively high proportion of European ancestry. The investigation and deposit of clinically relevant findings of diverse populations is fundamental improve this scenario.
Start page
357
End page
363
Volume
187
Issue
3
Language
English
OCDE Knowledge area
Genética humana
Subjects
Scopus EID
2-s2.0-85108955577
PubMed ID
Source
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics
ISSN of the container
1552-4868
Sponsor(s)
Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant/Award Number: 465355/2014‐5; Fundação de Amparo à Pesquisa do Estado de São Paulo, Grant/Award Numbers: 2013/08028‐1, 2014/50649‐6, 2014/50931‐3; National Institute of General Medical Sciences, Grant/Award Number: R01 GM075091 Funding information
The authors thank SABE participants for their long‐term contribution to science and Prof. Maria Lúcia Lebrão (in memoriam) for her conceptualization and conduction of SABE. Funding was provided by FAPESP grants (CEPID 2013/08028‐1, SABE 2014/50649‐6, INCT 2014/50931‐3) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq INCT 465355/2014‐5). The authors thank the Human Longevity Inc. team that supported and conducted whole‐genome sequencing. The authors acknowledge all the staff from the Human Genome and Stem Cell Research Center and Public Health School.
Sources of information:
Directorio de Producción Científica
Scopus