Molecular diagnosis of Hereditary Angioedema patients using a 77-gene NGS panel.
To be presented by Lili Wan, PhD at the 2023 American Academy of Allergy, Asthma, and Immunology Meeting in San Antonio, TX, 2/25/2023.
Hereditary Angioedema (HAE) is a rare autosomal dominant genetic disease frequently caused by mutations in the C1 inhibitor gene SERPING1, resulting in dysregulated kallikrein–kinin system (KKS) and overproduction of bradykinin. Despite a constellation of pathogenic mutations identified in SERPING1 and 5 others genes in the KKS pathway, genetic diagnosis of some patients with unknown HAE causing mutations but clear HAE clinical presentations are elusive. Genetic modifiers that may contribute to disease severity remains to be investigated. We carried out a pilot study to provide molecular diagnosis for HAE patients using a custom designed 77 gene Next Generation Sequencing (NGS) panel.
Genomic DNA is extracted from peripheral blood and screened for mutations using a custom 77 gene NGS panel. Exon level duplications/deletions were identified using multiplex ligation dependent probe amplification. The impact of variants was evaluated using commercial and publicly available computational tools.
Among the 81 samples sequenced [52 HAE, 26 non-HAE, 3 healthy controls], we found pathogenic SERPING1 mutations in 50 (96%)
of the 52 HAE samples, including a gross heterozygous deletion of exons 1-6. Additional variants of unknown significance meeting computational and segregation analysis criteria were identified as potentially impacting genotype-phenotype in two large families. Additional variants identified in
our NGS panel suggest possible HAE disease modifying genes that
corelate with phenotypic severity.
We designed and validated a comprehensive HAE molecular diagnosis workflow that has the potential to improve clinical diagnosis and assist in treatment option selections.