NEW YORK (GenomeWeb) – Next-generation sequencing could be a useful first-line tool to diagnose patients with primary antibody deficiency, according to a new study.
Primary antibody deficiency (PAD) is the most common form of primary immunodeficiency (PID), as it affects about 1 in every 600 people, and the second most common human immune system disorder after HIV infection. But the condition is marked by a range of overlapping symptoms and its presentation often varies by severity of the associated pathogenic variant.
While next-generation sequencing panels targeted to known PID genes have been used to screen patients as a first step toward diagnosis, this approach has had a low clinical sensitivity, according to a Karolinska Institute-led team of researchers. In a new study published in Genetics in Medicine this week, the researchers used exome sequencing to identify disease-related mutations in 68 percent of their 126 PAD patients.
"We suggest that NGS could replace a conventional multi-step genetic approach because it can be expanded to cover all known PID-associated genes and potentially detect CNVs and new genes associated with PID," Karolinska's Lennart Hammarström and his colleagues wrote in their paper.
The researchers recruited 126 unrelated individuals, mostly children and adolescents, of Middle Eastern ethnicity with undefined PAD to their study. Of these, 81 were classified as having common variable immunodeficiency, 11 an unsolved agammaglobulinemia, 14 an unsolved hyper IgM syndrome, 11 an IgAD deficiency, and nine another type of PAD. Nearly 83 percent of the individuals had parents who were related.
Exome sequencing analysis yielded a genetic diagnosis in 86 of the 126 patients. Forty-seven of these patients had pathogenic variants as well as the expected phenotypes. However, 37 patients had variants in known PID genes but exhibited uncharacteristic phenotypes, and two patients had variants newly implicated in the disease. Forty patients had no diagnosis.
The researchers noted that the lowest diagnostic yield was for patients with agammaglobulinemia.
Despite most of the patients' parents being biologically related, the researchers found that only slightly more than two-thirds of the genes had a recessive inheritance and only three were X-linked.
For 26 of the patients who received a genetic diagnosis, the researchers reported a change in disease management, switching from Ig replacement to a hematopoietic stem cell transplant. For another 15 patients with variants in DNA repair system genes, cancer screenings were added to their routine management. Exome sequencing also informed 49 families who were seeking family counseling and led to a prenatal diagnosis for 25 families.
Overall, the researchers reported that a genetic diagnosis affected the clinical treatment and management of nearly half the probands for whom a pathogenic variant was found.
Hammarström and his colleagues further estimated that they would not have been able to uncover the disease-causing variants in about 40 percent of the patients in whom they did find a diagnosis if they had relied solely on targeted sequencing. Based on this, they suggested that a high-throughput genomic approach should be a first screening step for PAD patients.
"[E]mploying next-generation sequencing as a preliminary step of molecular diagnostic approach to patients with PAD is crucial for management and treatment of the patients and their family members," they wrote.