Comprehensive genetic testing for primary immunodeficiency disorders in a tertiary hospital: 10-year experience in Auckland, New Zealand

Abstract

Background and purposeNew Zealand is a developed geographically isolated country in the South Pacific with a population of 4.4 million. Genetic diagnosis is the standard of care for most patients with primary immunodeficiency disorders (PIDs).MethodsSince 2005, we have offered a comprehensive genetic testing service for PIDs and other immune-related disorders with a published sequence. Here we present results for this program, over the first decade, between 2005 and 2014.ResultsWe undertook testing in 228 index cases and 32 carriers during this time. The three most common test requests were for X-linked lymphoproliferative (XLP), tumour necrosis factor receptor associated periodic syndrome (TRAPS) and haemophagocytic lymphohistiocytosis (HLH). Of the 32 suspected XLP cases, positive diagnoses were established in only 2 patients. In contrast, genetic defects in 8 of 11 patients with suspected X-linked agammaglobulinemia (XLA) were confirmed. Most XLA patients were initially identified from absence of B cells. Overall, positive diagnoses were made in about 23% of all tests requested. The diagnostic rate was lowest for several conditions with locus heterogeneity.ConclusionsThorough clinical characterisation of patients can assist in prioritising which genes should be tested. The clinician-driven customised comprehensive genetic service has worked effectively for New Zealand. Next generation sequencing will play an increasing role in disorders with locus heterogeneity.

Comprehensive Genetic Results for Primary Immunodeficiency Disorders in a Highly Consanguineous Population

“…The overall genetic diagnostic yield in our study was 70%. This is slightly lower than a yield of 81% in a study done in Iran, but higher than the yield in studies done in New Zealand (23%) and China (40%) (26, 37, 38). This can be due to differences in the technology used for genetic sequencing studies, the study population, and the number of genes studied.…”

Clinical Implications of Digenic Inheritance and Epistasis in Primary Immunodeficiency Disorders

“…If there is a discrepancy in the segregation analysis, there may be another unidentified mutation, as seen in our family. It is likely the first mutation will be identified by Sanger sequencing of a candidate gene ( 33 ) and the second mutation will be obtained by NGS-based gene discovery techniques.…”

All Patients With Common Variable Immunodeficiency Disorders (CVID) Should Be Routinely Offered Diagnostic Genetic Testing

“…The advent of NGS is the principal reason for the feasibility of routine genetic sequencing of patients with CVID-like disorders, who have locus heterogeneity (33). A similar approach is now being undertaken for other disorders with locus heterogeneity such at atypical hemolytic uremic syndrome (aHUS) and hemophagocytic lymphohistiocytosis (HLH) (34).…”