A new international study published in the Journal of Allergy and Clinical Immunology suggests that the KIT D816V mutation, which is known to drive systemic mastocytosis (SM) and other clonal mast cell diseases, is more common among people who experience anaphylaxis or systemic mast cell activation (MCA) symptoms than previously thought. The results suggest that testing for the KIT D816V mutation in peripheral blood could help identify undiagnosed cases of SM or related disorders much earlier.
What is a KIT gene mutation?
SM is usually caused by a sporadic mutation in the KIT gene, which codes for a protein called CD117 transmembrane tyrosine kinase. The protein is involved in the growth, survival and migration of mast cells. The most common KIT mutation associated with SM is the D816V mutation, which results in the amino acid aspartic acid being replaced by the amino acid valine in the protein chain.
The study included 381 adults in the United States and Europe who had experienced anaphylaxis or symptoms consistent with systemic MCA. Participants were grouped based on the type and severity of their reactions, including those with serious reactions to Hymenoptera (bee, wasp or hornet) stings, those with significant tryptase increases during anaphylaxis and those with cardiovascular and multi-organ involvement alongside elevated baseline tryptase (≥8 ng/mL).
Researchers analyzed blood samples for the KIT D816V mutation, hereditary alpha-tryptasemia (HaT) and tryptase levels. The results showed that 4% of participants had the KIT D816V mutation detected in their peripheral blood. Notably, 80% of these individuals had basal serum tryptase levels below 20 ng/mL (the traditional cutoff used in SM diagnosis), showing that patients with normal or only slightly elevated tryptase levels can still be impacted by clonal mast cell disease.
Most of the individuals with KIT D816V (73%) had severe, life-threatening anaphylaxis. When local follow-up was included, another 14 patients were diagnosed with cMCD, meaning that roughly 8% of the study population had an underlying mast cell disorder.
Learn more about SM causes and risk factors
The researchers found HaT in 36% of participants, a rate much higher than in the general population. While HaT can raise tryptase levels, it was not clearly linked to more severe anaphylaxis in this study. Only one patient had both HaT and the KIT D816V mutation.
The findings show that relying solely on traditional markers, such as elevated tryptase above 20 ng/mL, may cause clinicians to miss cases of cMCD.
According to the authors, screening for KIT D816V mutations in people with moderate-to-severe anaphylaxis, especially those with cardiovascular symptoms or reactions to insect stings, should become more routine. Earlier identification of the mutation could improve diagnosis of SM and related mast cell disorders, conditions that often go undetected until years after symptom onset.
“Additional studies leveraging variant enrichment strategies and/or utilizing higher-sensitivity assays may be required to more accurately detect the KIT D816V mutation in patients with anaphylaxis, symptoms consistent with systemic MCA, and other populations,” the authors concluded.
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