Rare Genetic Variations in KNG1, XPNPEP1 Linked to HAE With Normal C1-INH
Variations in the genes KNG1 and XPNPEP1 may be associated with hereditary angioedema (HAE) that occurs in people without any of the mutations that typically cause the disease, a new study suggests.
The preliminary findings highlight the genetic complexity of HAE, researchers said.
The study, “Deciphering the Genetics of Primary Angioedema with Normal Levels of C1 Inhibitor,” was published in the Journal of Clinical Medicine.
The classical HAE types — known as types 1 and 2 — are caused by mutations in the SERPING1 gene, which codes for the protein C1 inhibitor, called C1-INH. When patients lack these mutations, they have an extremely rare subtype called HAE type 3.
Until recently, mutations in the F12 gene were the only known genetic causes of type 3 HAE. Mutations in two other genes — ANGPT1 and PLG — also have been associated in the past few years with this type of angioedema.
Still, a large proportion of HAE cases occur in people who don’t have any of these known mutations.
Now, to better understand the genetic underpinnings of these cases, a team of European researchers analyzed 55 genes that, based on their known biological function, could purportedly be connected to HAE.
These genes were sequenced in 133 unrelated people with HAE who had normal C1-INH levels and function. These patients were known as the nl-C1-INH-HAE group, or the type 3 HAE group. For comparison, the investigators also assessed 169 patients with HAE caused by missing or defective C1-INH; this was the C1-INH-HAE group.
In total, 182 different genetic variants were identified in the 55 genes. Of note, 21 of these variants have never before been reported in the literature.
Most of these genetic variations were just as common in people with or without a normal C1-INH. However, six variants in the gene KNG1 and three variants in the gene XPNPEP1 were detected in the nl-C1-INH-HAE group — whereas no variants in these genes were detected in the C1-INH-HAE group.
Of note, a variation in KNG1 was associated with angioedema in a previous study, though that exact variant was not identified in this study.
“These findings indicate that variations in the KNG1 gene could contribute to the pathogenesis of the disease; thus, they deserve further consideration,” the researchers wrote.
An in-depth analysis of the individual patients and each of their genes revealed some insights of interest. For instance, two of the analyzed individuals, a mother and her daughter, had the same series of variations in seven different genes.
“This observation suggests that, at least in certain cases, nl-C1-INH-HAE could be the result of the cumulative effect of multiple gene variations,” the researchers wrote.
“Taken together, [these findings] clearly demonstrate that, genetically, nl-C1-INH-HAE is an extremely complex disorder,” the researchers concluded.
The investigators cautioned that this study is limited by the small sample size, and by the fact that, in many cases, it wasn’t possible to analyze the genetics of unaffected family members. Since genetic variations run in families, determining whether people who have a particular gene also have angioedema can be helpful in determining whether a variant is truly disease-causing.
“Thus, strong evidence of the causative effect of certain variants has not been provided,” the researchers wrote. “Nevertheless, the results of the study helpfully highlight the role that alterations in some genes, like KNG1, may play in the pathogenesis [development] of the disease.”