Biased pathogenic assertions of loss of function variants challenge molecular diagnosis of admixed individuals

Autor(es):Mostrar menos -

Naslavsky, Michel S. ^{[1, 2, 3]} ; Scliar, Marilia O. ^[3] ; Nunes, Kelly ^[2] ; Wang, Jaqueline Y. T. ^[3] ; Yamamoto, Guilherme L. ^{[4, 3, 5, 6, 7]} ; Guio, Heinner ^{[8, 9]} ; Tarazona-Santos, Eduardo ^{[10, 11, 12, 13]} ; Duarte, Yeda A. O. ^{[14, 15]} ; Passos-Bueno, Maria Rita ^{[2, 3]} ; Meyer, Diogo ^[2] ; Zatz, Mayana ^{[2, 3]}

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^[1] Hosp Israelita Albert Einstein, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Biosci Inst, Dept Genet & Evolutionary Biol, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Human Genome & Stem Cell Res Ctr, Rua Matao 277-211, BR-05508090 Sao Paulo, SP - Brazil

^[4] Harvard Med Sch, Dept Genet, Boston, MA 02115 - USA

^[5] Univ Sao Paulo, Fac Med, Inst Crianca, Sao Paulo, SP - Brazil

^[6] Harvard Med Sch, Boston Childrens Hosp, Orthoped Res Labs, Boston, MA 02115 - USA

^[7] Lab DASA, Sao Paulo, SP - Brazil

^[8] Inst Nacl Salud, Lima - Peru

^[9] Univ Huanuco, Huanuco - Peru

^[10] Univ Peruana Cayetano Heredia, Fac Salud Publ & Adm, Lima - Peru

^[11] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Genet Ecol & Evolucao, Belo Horizonte, MG - Brazil

^[12] Univ Fed Minas Gerais, Mosaico Translat Genom Initiat, Belo Horizonte, MG - Brazil

^[13] Univ Fed Minas Gerais, Inst Estudos Avancados Transdisciplinares, Belo Horizonte, MG - Brazil

^[14] Univ Sao Paulo, Sch Nursing, Med Surg Nursing Dept, Sao Paulo, SP - Brazil

^[15] Univ Sao Paulo, Publ Hlth Sch, Epidemiol Dept, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS; v. 187, n. 3, SI, p. 357-363, SEP 2021.
• Citações Web of Science: 0

Resumo

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 Sao 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. (AU)

• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 14/50649-6 - Estudo SABE: estudo longitudinal de múltiplas coortes sobre as condições de vida e saúde dos idosos do município de São Paulo - coorte 2015
• Beneficiário: Yeda Aparecida de Oliveira Duarte
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 14/50931-3 - INCT 2014 - Envelhecimento e Doenças Genéticas: Genômica e Metagenômica
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Temático