TY - JOUR
T1 - A Novel Targeted Amplicon Next-Generation Sequencing Gene Panel for the Diagnosis of Common Variable Immunodeficiency Has a High Diagnostic Yield
T2 - Results from the Perth CVID Cohort Study
AU - Kermode, William
AU - De Santis, Dianne
AU - Truong, Linh
AU - Della Mina, Erika
AU - Salman, Sam
AU - Thompson, Grace
AU - Nolan, David
AU - Loh, Richard
AU - Mallon, Dominic
AU - Mclean-Tooke, Andrew
AU - John, Mina
AU - Tangye, Stuart G.
AU - O'Sullivan, Michael
AU - D'Orsogna, Lloyd J.
N1 - Funding Information:
The Tangye Lab is supported by grants awarded by the National Health and Medical Research Council (NHMRC) of Australia. S.G.T. was a Principal Research Fellow (1042925) of the NHMRC , and is currently a recipient of an NHMRC Leadership 3 Investigator grant (1176665) and NHMRC program grant (1113904).
Publisher Copyright:
© 2022
PY - 2022/6
Y1 - 2022/6
N2 - With the advent of next-generation sequencing (NGS), monogenic forms of common variable immunodeficiency (CVID) have been increasingly described. Our study aimed to identify disease-causing variants in a Western Australian CVID cohort using a novel targeted NGS panel. Targeted amplicon NGS was performed on 22 unrelated subjects who met the formal European Society for Immunodeficiencies–Pan-American Group for Immunodeficiency diagnostic criteria for CVID and had at least one of the following additional criteria: disease onset at age <18 years, autoimmunity, low memory B lymphocytes, family history, and/or history of lymphoproliferation. Candidate variants were assessed by in silico predictions of deleteriousness, comparison to the literature, and classified according to the American College of Medical Genetics and Genomics–Association for Molecular Pathology criteria. All detected genetic variants were verified independently by an external laboratory, and additional functional studies were performed if required. Pathogenic or likely pathogenic variants were detected in 6 of 22 (27%) patients. Monoallelic variants of uncertain significance were also identified in a further 4 of 22 patients (18%). Pathogenic variants, likely pathogenic variants, or variants of uncertain significance were found in TNFRSF13B, TNFRSF13C, ICOS, AICDA, IL21R, NFKB2, and CD40LG, including novel variants and variants with unexpected inheritance pattern. Targeted amplicon NGS is an effective tool to identify monogenic disease-causing variants in CVID, and is comparable or superior to other NGS methods. Moreover, targeted amplicon NGS identified patients who may benefit from targeted therapeutic strategies and had important implications for family members.
AB - With the advent of next-generation sequencing (NGS), monogenic forms of common variable immunodeficiency (CVID) have been increasingly described. Our study aimed to identify disease-causing variants in a Western Australian CVID cohort using a novel targeted NGS panel. Targeted amplicon NGS was performed on 22 unrelated subjects who met the formal European Society for Immunodeficiencies–Pan-American Group for Immunodeficiency diagnostic criteria for CVID and had at least one of the following additional criteria: disease onset at age <18 years, autoimmunity, low memory B lymphocytes, family history, and/or history of lymphoproliferation. Candidate variants were assessed by in silico predictions of deleteriousness, comparison to the literature, and classified according to the American College of Medical Genetics and Genomics–Association for Molecular Pathology criteria. All detected genetic variants were verified independently by an external laboratory, and additional functional studies were performed if required. Pathogenic or likely pathogenic variants were detected in 6 of 22 (27%) patients. Monoallelic variants of uncertain significance were also identified in a further 4 of 22 patients (18%). Pathogenic variants, likely pathogenic variants, or variants of uncertain significance were found in TNFRSF13B, TNFRSF13C, ICOS, AICDA, IL21R, NFKB2, and CD40LG, including novel variants and variants with unexpected inheritance pattern. Targeted amplicon NGS is an effective tool to identify monogenic disease-causing variants in CVID, and is comparable or superior to other NGS methods. Moreover, targeted amplicon NGS identified patients who may benefit from targeted therapeutic strategies and had important implications for family members.
UR - http://www.scopus.com/inward/record.url?scp=85131430768&partnerID=8YFLogxK
U2 - 10.1016/j.jmoldx.2022.02.007
DO - 10.1016/j.jmoldx.2022.02.007
M3 - Article
C2 - 35570134
SN - 1525-1578
VL - 24
SP - 586
EP - 599
JO - The Journal of Molecular Diagnostics
JF - The Journal of Molecular Diagnostics
IS - 6
ER -