Clinical Utility of Whole Exome Sequencing and Targeted Panels for the Identification of Inborn Errors of Immunity in a Resource-Constrained Setting

Abstract

Primary immunodeficiency disorders (PIDs) are inborn errors of immunity (IEI) that cause immune system impairment. To date, more than 400 single-gene IEI have been well defined. The advent of next generation sequencing (NGS) technologies has improved clinical diagnosis and allowed for discovery of novel genes and variants associated with IEI. Molecular diagnosis provides clear clinical benefits for patients by altering management, enabling access to certain treatments and facilitates genetic counselling. Here we report on an 8-year experience using two different NGS technologies, namely research-based WES and targeted gene panels, in patients with suspected IEI in the South African healthcare system. A total of 52 patients’ had WES only, 26 had a targeted gene panel only, and 2 had both panel and WES. Overall, a molecular diagnosis was achieved in 30% (24/80) of patients. Clinical management was significantly altered in 67% of patients following molecular results. All 24 families with a molecular diagnosis received more accurate genetic counselling and family cascade testing. Results highlight the clinical value of expanded genetic testing in IEI and its relevance to understanding the genetic and clinical spectrum of the IEI-related disorders in Africa. Detection rates under 40% illustrate the complexity and heterogeneity of these disorders, especially in an African population, thus highlighting the need for expanded genomic testing and research to further elucidate this.

Guideline for feedback of individual genetic research findings for genomics research in Africa

“…Programmes such as ClinGen and ClinVar use combinations of evidence from clinical and public health data, basic science and in silico research to identify and curate genetic variants with clinical utility. 28 29 Engelbrehct et al demonstrated clinical utility of sequencing panels in improving management of primary immunodeficiency disorders in an African 30 It is important to note that clinical utility does not guarantee actionability, especially in Africa, where limited access to resources could limit provision of appropriate care. However, the information may be useful in understanding diagnosis or making reproductive decisions.…”

Mendelian susceptibility to mycobacterial disease in tuberculosis-hyperendemic South Africa

“…[1,2,7] The application of WES in this cohort of patients confirmed a molecular diagnosis in just over one-third of patients, in keeping with international and local identification of a molecular diagnosis with the application of NGS, 40% and 30%, respectively. [17,18] Sensitivity for NGS in undiagnosed PIDD has been reported to range from 83% to 100%, while specificity ranges from 45% to 99%. [2,17] The diagnostic yield depends largely on the population as well as the technical skill with which and the circumstances under which NGS is employed.…”

“…[2,17] The diagnostic yield depends largely on the population as well as the technical skill with which and the circumstances under which NGS is employed. [2,17,18] Using WES and whole-genome sequencing (WGS) to diagnose rare and understudied diseases remains a challenge that is further complicated when done in a population with a poorly defined reference genome, such as South Africans. [7,13,18] The large amounts of data generated by WGS and WES that require highly skilled interpretation complicate their use in routine clinical practice, so clinically guided PIDD panels are generally preferred in the initial diagnostic work-up.…”

“…[2,17,18] Using WES and whole-genome sequencing (WGS) to diagnose rare and understudied diseases remains a challenge that is further complicated when done in a population with a poorly defined reference genome, such as South Africans. [7,13,18] The large amounts of data generated by WGS and WES that require highly skilled interpretation complicate their use in routine clinical practice, so clinically guided PIDD panels are generally preferred in the initial diagnostic work-up. [2,18] An MSMD-targeted gene panel should focus on mutations in the IFNGR1, IFNGR2, STAT1, CYBB, IRF8, NEMO, IL12B, IL12RB1 and IL12RB2 genes.…”

“…[7,13,18] The large amounts of data generated by WGS and WES that require highly skilled interpretation complicate their use in routine clinical practice, so clinically guided PIDD panels are generally preferred in the initial diagnostic work-up. [2,18] An MSMD-targeted gene panel should focus on mutations in the IFNGR1, IFNGR2, STAT1, CYBB, IRF8, NEMO, IL12B, IL12RB1 and IL12RB2 genes. [1,9,10] In SA, WES and WGS are generally only available on a research basis owing to limited funding for genomic medicine.…”