Cargando…

Novel alleles in the era of next-generation sequencing-based HLA typing calls for standardization and policy

Next-Generation Sequencing (NGS) has transformed clinical histocompatibility laboratories through its capacity to provide accurate, high-throughput, high-resolution typing of Human Leukocyte Antigen (HLA) genes, which is critical for transplant safety and success. As this technology becomes widely u...

Descripción completa

Detalles Bibliográficos
Autores principales: Tran, Jenny N., Sherwood, Karen R., Mostafa, Ahmed, Benedicto, Rey Vincent, ElaAlim, Allaa, Greenshields, Anna, Keown, Paul, Liwski, Robert, Lan, James H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10611506/
https://www.ncbi.nlm.nih.gov/pubmed/37900182
http://dx.doi.org/10.3389/fgene.2023.1282834
_version_ 1785128504090689536
author Tran, Jenny N.
Sherwood, Karen R.
Mostafa, Ahmed
Benedicto, Rey Vincent
ElaAlim, Allaa
Greenshields, Anna
Keown, Paul
Liwski, Robert
Lan, James H.
author_facet Tran, Jenny N.
Sherwood, Karen R.
Mostafa, Ahmed
Benedicto, Rey Vincent
ElaAlim, Allaa
Greenshields, Anna
Keown, Paul
Liwski, Robert
Lan, James H.
author_sort Tran, Jenny N.
collection PubMed
description Next-Generation Sequencing (NGS) has transformed clinical histocompatibility laboratories through its capacity to provide accurate, high-throughput, high-resolution typing of Human Leukocyte Antigen (HLA) genes, which is critical for transplant safety and success. As this technology becomes widely used for clinical genotyping, histocompatibility laboratories now have an increased capability to identify novel HLA alleles that previously would not be detected using traditional genotyping methods. Standard guidelines for the clinical verification and reporting of novelties in the era of NGS are greatly needed. Here, we describe the experience of a clinical histocompatibility laboratory’s use of NGS for HLA genotyping and its management of novel alleles detected in an ethnically-diverse population of British Columbia, Canada. Over a period of 18 months, 3,450 clinical samples collected for the purpose of solid organ or hematopoietic stem cell transplantation were sequenced using NGS. Overall, 29 unique novel alleles were identified at a rate of ∼1.6 per month. The majority of novelties (52%) were detected in the alpha chains of class II (HLA-DQA1 and -DPA1). Novelties were found in all 11 HLA classical genes except for HLA-DRB3, -DRB4, and -DQB1. All novelties were single nucleotide polymorphisms, where more than half led to an amino acid change, and one resulted in a premature stop codon. Missense mutations were evaluated for changes in their amino acid properties to assess the potential effect on the novel HLA protein. All novelties identified were confirmed independently at another accredited HLA laboratory using a different NGS assay and platform to ensure validity in the reporting of novelties. The novel alleles were submitted to the Immuno Polymorphism Database-Immunogenetics/HLA (IPD-IMGT/HLA) for official allele name designation and inclusion in future database releases. A nationwide survey involving all Canadian HLA laboratories confirmed the common occurrence of novel allele detection but identified a wide variability in the assessment and reporting of novelties. In summary, a considerable proportion of novel alleles were identified in routine clinical testing. We propose a framework for the standardization of policies on the clinical management of novel alleles and inclusion in proficiency testing programs in the era of NGS-based HLA genotyping.
format Online
Article
Text
id pubmed-10611506
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-106115062023-10-28 Novel alleles in the era of next-generation sequencing-based HLA typing calls for standardization and policy Tran, Jenny N. Sherwood, Karen R. Mostafa, Ahmed Benedicto, Rey Vincent ElaAlim, Allaa Greenshields, Anna Keown, Paul Liwski, Robert Lan, James H. Front Genet Genetics Next-Generation Sequencing (NGS) has transformed clinical histocompatibility laboratories through its capacity to provide accurate, high-throughput, high-resolution typing of Human Leukocyte Antigen (HLA) genes, which is critical for transplant safety and success. As this technology becomes widely used for clinical genotyping, histocompatibility laboratories now have an increased capability to identify novel HLA alleles that previously would not be detected using traditional genotyping methods. Standard guidelines for the clinical verification and reporting of novelties in the era of NGS are greatly needed. Here, we describe the experience of a clinical histocompatibility laboratory’s use of NGS for HLA genotyping and its management of novel alleles detected in an ethnically-diverse population of British Columbia, Canada. Over a period of 18 months, 3,450 clinical samples collected for the purpose of solid organ or hematopoietic stem cell transplantation were sequenced using NGS. Overall, 29 unique novel alleles were identified at a rate of ∼1.6 per month. The majority of novelties (52%) were detected in the alpha chains of class II (HLA-DQA1 and -DPA1). Novelties were found in all 11 HLA classical genes except for HLA-DRB3, -DRB4, and -DQB1. All novelties were single nucleotide polymorphisms, where more than half led to an amino acid change, and one resulted in a premature stop codon. Missense mutations were evaluated for changes in their amino acid properties to assess the potential effect on the novel HLA protein. All novelties identified were confirmed independently at another accredited HLA laboratory using a different NGS assay and platform to ensure validity in the reporting of novelties. The novel alleles were submitted to the Immuno Polymorphism Database-Immunogenetics/HLA (IPD-IMGT/HLA) for official allele name designation and inclusion in future database releases. A nationwide survey involving all Canadian HLA laboratories confirmed the common occurrence of novel allele detection but identified a wide variability in the assessment and reporting of novelties. In summary, a considerable proportion of novel alleles were identified in routine clinical testing. We propose a framework for the standardization of policies on the clinical management of novel alleles and inclusion in proficiency testing programs in the era of NGS-based HLA genotyping. Frontiers Media S.A. 2023-10-13 /pmc/articles/PMC10611506/ /pubmed/37900182 http://dx.doi.org/10.3389/fgene.2023.1282834 Text en Copyright © 2023 Tran, Sherwood, Mostafa, Benedicto, ElaAlim, Greenshields, Keown, Liwski and Lan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Tran, Jenny N.
Sherwood, Karen R.
Mostafa, Ahmed
Benedicto, Rey Vincent
ElaAlim, Allaa
Greenshields, Anna
Keown, Paul
Liwski, Robert
Lan, James H.
Novel alleles in the era of next-generation sequencing-based HLA typing calls for standardization and policy
title Novel alleles in the era of next-generation sequencing-based HLA typing calls for standardization and policy
title_full Novel alleles in the era of next-generation sequencing-based HLA typing calls for standardization and policy
title_fullStr Novel alleles in the era of next-generation sequencing-based HLA typing calls for standardization and policy
title_full_unstemmed Novel alleles in the era of next-generation sequencing-based HLA typing calls for standardization and policy
title_short Novel alleles in the era of next-generation sequencing-based HLA typing calls for standardization and policy
title_sort novel alleles in the era of next-generation sequencing-based hla typing calls for standardization and policy
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10611506/
https://www.ncbi.nlm.nih.gov/pubmed/37900182
http://dx.doi.org/10.3389/fgene.2023.1282834
work_keys_str_mv AT tranjennyn novelallelesintheeraofnextgenerationsequencingbasedhlatypingcallsforstandardizationandpolicy
AT sherwoodkarenr novelallelesintheeraofnextgenerationsequencingbasedhlatypingcallsforstandardizationandpolicy
AT mostafaahmed novelallelesintheeraofnextgenerationsequencingbasedhlatypingcallsforstandardizationandpolicy
AT benedictoreyvincent novelallelesintheeraofnextgenerationsequencingbasedhlatypingcallsforstandardizationandpolicy
AT elaalimallaa novelallelesintheeraofnextgenerationsequencingbasedhlatypingcallsforstandardizationandpolicy
AT greenshieldsanna novelallelesintheeraofnextgenerationsequencingbasedhlatypingcallsforstandardizationandpolicy
AT keownpaul novelallelesintheeraofnextgenerationsequencingbasedhlatypingcallsforstandardizationandpolicy
AT liwskirobert novelallelesintheeraofnextgenerationsequencingbasedhlatypingcallsforstandardizationandpolicy
AT lanjamesh novelallelesintheeraofnextgenerationsequencingbasedhlatypingcallsforstandardizationandpolicy