30 May 2022

A novel form of gene sequencing can effectively identify immune disease-causing genetic variants, scientists report.

The new method can highlight patients who may benefit from targeted therapeutic strategies, and has important implications for family members, the research team state in The Journal of Molecular Diagnostics.

Common Variable Immunodeficiency (CVID) causes low levels of immune proteins and leads to repeated ear, sinus and respiratory infections, as well as a raised risk of digestive disorders, autoimmune disorders, blood disorders and cancer.

A form of next-generation gene sequencing called 'targeted amplicon' sequencing is able to read the DNA code of multiple genes of a person at low cost, researchers say, which makes it useful for identifying gene variants linked to CVID.

The new study aimed to identify such gene variants in samples from 22 unrelated patients in Western Australia, using a novel sequencing panel of 120 genes.

A number of disease-causing gene variants were discovered and verified by an external laboratory. Disease-causing (or probable disease-causing) variants were found in 6 of the 22 patients (27%), with gene variants "of uncertain significance" found in a further four patients (18%).

The authors write: “Pathogenic variants, likely pathogenic variants, or variants of uncertain significance were found in the genes TNFRSF13B, TNFRSF13C, ICOS, AICDA, IL21R, NFKB2, and CD40LG.”

They believe: “Targeted amplicon next-generation sequencing is an effective tool to identify monogenic disease-causing variants in common variable immunodeficiency. It can be used as a suitable genetic test for diagnosis in patients with common variable immunodeficiency.

“A confirmed genetic diagnosis in the patients included in this study enabled additional options for genetic counselling and family planning and could have provided the opportunity for life-saving targeted therapy.”

Dr Lloyd D’Orsogna of the University of Western Australia, who led the study, said: “We can identify a specific gene that may lead to frequent infections in patients. An earlier and more accurate diagnosis may improve the patient outcome and prevent complications.”

Source: Kermode W, De Santis D, Truong L, Della Mina E, Salman S, Thompson G, Nolan D, Loh R, Mallon D, Mclean-Tooke A, John M, Tangye SG, O'Sullivan M, D'Orsogna LJ. (2022) “A Novel Targeted Amplicon Next-Generation Sequencing Gene Panel for the Diagnosis of Common Variable Immunodeficiency Has a High Diagnostic Yield: Results from the Perth CVID Cohort Study.” Journal of Molecular Diagnostics, doi: 10.1016/j.jmoldx.2022.02.007

Link: https://www.jmdjournal.org/article/S1525-1578(22)00078-2/fulltext

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