Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants
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Fecha
2014-10-02Autor(es)
Shearer, Aiden EliotEppsteiner, Robert
Booth, Kevin
Ephraim, Sean
Gurrola, José
Simpson, Allen
Black Ziegelbein, Ann
Swati, Joshi
Ravi, Harini
Giuffre, Angelica
Happe, Scott
Hildebrand, Michael
Azaiez, Hela
Bayazit, Yildirim
Erdal, Mehmet Emin
López Escamez, José Antonio
Gazquez, Irene
Tamayo Fernández, Marta Lucía
Gelvez Moyano, Nancy Yaneth
López Leal, Greizy
Jalas, Chaim
Ekstein, Josef
Yang, Tao
Usami, Shin-Ichi
Kahrizi, Kimia
Bazazzadegan, Niloofar
Najmabadi, Hossein
Scheetz, Todd
Braun, Terry
Casavant, Thomas
LeProust, Emily
Smith, Richard
Autor(es) Corporativo(s)
Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana
Tipo
Artículo de revista
ISSN
0002-9297 / 1537-6605 (Electrónico)
Páginas
445-453
Tipo de artículo
Artículo original
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Título en inglés
Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variantsAbstract
Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) >0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness.
Enlace al recurso
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185121/Fuente
The American Journal of Human Genetics; Vol. 95 Núm. 4 (2014)
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