During the last years, the genetic etiology of an increasing number of inborn errors of immunity (IEIs) has been elucidated, establishing unequivocal diagnoses and enabling accurate genetic counseling. However, genetic heterogeneity of most IEIs is high and patients frequently had to be assessed for more than one gene, anyway remaining without a disease-causing genotype. Next Generation Sequencing (NGS) allows evaluation of a large number of genes at the same time on several patients in parallel.
According to our previous data from “the Sanger era”, the lowest diagnostic yield occurred in those patients displaying immune dysregulation diseases (with 9 genes evaluated), autoinflammatory disorders (3 genes analyzed) or defects in innate immunity (4 different genes). Since 2017, our patients with these clinical phenotypes can take advantage of a custom panel of up to 333 genes.
From our cohort of 292 index cases referred for molecular studies by NGS custom gene panels, we performed a retrospective evaluation aiming to examine how many of them reached a definite or highly probable diagnosis of IEI.
Twenty-eight percent of them (80/292) achieved a confirmed or highly probable genetic etiology. According to IEIs categories diseases of immune dysregulation attained 28% (30/107) of these diagnoses, autoinflammatory disorders 19% (12/63) and defects in innate immunity 5% (2/38). It is also important to note that for instance in patients with suspected immune dysregulation by increasing to 51 the number of genes simultaneously analyzed, highly probable pathogenic variants in 17 unique genes could be revealed.
Beyond the number of confirmed diagnoses, NGS dramatically reduced the response time, important for an accurate disease management by increasing at the same time gene analysis scope.
In addition to family segregation studies that took into account the type of inheritance involved, functional studies had to be incorporated to confirm the pathogenicity of some variants.