Disruptive Germline Variants Do Not Drive Adult-onset HLH, Study Suggests

Disruptive Germline Variants Do Not Drive Adult-onset HLH, Study Suggests

Germline variants — genetic mutations found in sperm or eggs that can be passed down to offspring — associated with hemophagocytic lymphohistiocytosis (HLH) are not more prevalent in patients with adult-onset forms of the condition, nor are they associated with a specific set of clinical features, a study says.

The study, “Identification of germline variants in adults with hemophagocytic lymphohistiocytosis,” was published in the journal Blood Advances.

HLH, a disease characterized by an overactivation of the immune system, is considered primary (familial) when it is caused by mutations in specific genes that control the activity of the immune system, or secondary (acquired) when it is associated with other medical conditions.

Studies based on mathematical algorithms predicted that certain germline variants associated with HLH are enriched in adults with the disease. However, these observations have been limited by the small number of patients and genes analyzed.

In addition, “the comparatively young ages at the time of HLH onset have made distinguishing FHL [familial HLH] that occurs in early adulthood from true adult-onset HLH difficult,” the researchers wrote.

To overcome these limitations, investigators at the Dana-Farber Cancer Institute and collaborators conducted a study to identify potential germline variants in 17 genes that had been associated with HLH in a group of 88 adults, ages 18–81, with the disease.

DNA was isolated from bone marrow aspirates or blood samples of the patients, all of whom met the HLH diagnostic criteria, HLH-2004, as defined by the Histiocyte Society.

More than half (77%) of the patients had an underlying medical condition that triggered the onset of HLH. The most common underlying condition was cancer (49%), followed by infections (30%), and autoimmune diseases (17%).

From the 17 genes analyzed, the investigators identified a total of 42 genetic variants in 45 patients participating in the study. Seven of these variants (found in 18 patients) were considered disruptive, meaning that they likely had a negative impact on the function of the protein encoded by the gene in which they were found.

PRF1 A91V, a genetic variant previously reported to impair immune cells’ cytotoxicity (ability to destroy other cells or microbes), was the most common disruptive genetic variant found in the study (found in 14% of participants). Three patients were also found to carry more than one disruptive genetic variant.

Then, to assess if the seven disruptive germline variants identified were more common in adults, the investigators compared the frequency of these variants in the group of adult patients analyzed with the frequency in a larger group of 2,504 patients who participated in 1000 Genome Project (TGP group).

The team found that these variants were much less common in the TGP group (5%) when compared with the group of adults with HLH (20%), “an unsurprising result given the rarity of individual variants,” the researchers wrote.

A similar finding was observed when they found a higher frequency of the disruptive variants in the group of adults with HLH (20%) compared with the frequency of any disruptive variant in the 17 genes analyzed in the TGP group (9%).

However, these differences were no longer significant when researchers compared data from patients belonging to the same ethnicity and geographical region.

Furthermore, after excluding patients with a PRF1 A91V variant, there was no difference in the frequency of patients with disruptive variants between our cohort and the TGP (4.4% in both groups),” they wrote.

In their final analyses, the researchers focused on investigating if these disruptive germline variants could be linked to a specific set of laboratory or clinical features. However, no associations were found between the presence of disruptive variants and patients’ age, sex, underlying condition, ferritin levels, and soluble interleukin 2 receptor levels.

“Our data suggest that disruptive germline variants do not drive adult HLH, unlike FHL,” the researchers wrote. “Furthermore, disruptive variants were not enriched in adult HLH compared with control when accounting for ancestry, particularly when considering non-PRF1 A91V variants. Additionally, there were no clinical differences between patients with and without disruptive variants.”

“Our data suggest that familial and adult-onset HLH have a distinct pathophysiology [disease mechanisms], and do not support routine germline testing of adults with HLH,” the team added, emphasizing, however, the “importance of testing for genetic variants in cases in which FHL is highly suspected (including strong family history and young age of onset).”