A case report of a man with systemic mastocytosis (SM) and a previously unknown KIT mutation was recently published in Virchows Archiv.
“Our case highlights the importance of exhaustive molecular genetic testing in patients with suspected SM in whom conventional tests and algorithms display shortages in identifying oncogenic variants,” the authors wrote.
In most cases, SM is driven by an activating mutation in the KIT gene. KIT encodes a receptor called tyrosine kinase, which is essential for mast cell development. Therefore, its activation plays a key role in the overproduction and activation of mast cells that characterizes SM.
The D816V mutation is the most common KIT mutation and is present in the majority of SM cases. However, other activating KIT variants have been reported and are included as a minor diagnostic criterion in the WHO classification of mastocytosis, a set of criteria used to diagnose the disease.
Read more about SM testing and diagnosis
The case involved a 37-year-old man with a history of anaphylaxis and persistent mast cell activation symptoms like frequent skin rashes and dizziness. These symptoms raised the suspicion of SM.
Despite elevated serum tryptase levels and a bone marrow biopsy showing characteristic CD25+ and tryptase-positive mast cell aggregates — all signs of SM — standard genetic testing for KIT D816V was negative.
Further analysis using next-generation sequencing (NGS) initially failed to detect any KIT variant. However, manual inspection of the sequencing data revealed a novel in-frame deletion-insertion mutation, D816_N819delinsll, affecting the same critical region as the typical D816V mutation.
The newly identified mutation leads to protein production changes which likely alter the receptor’s conformation and drive an abnormal ligand-independent KIT activation.
With this finding, the man was diagnosed with indolent SM. The authors remarked that this case reinforces the need for full sequencing of KIT in clinically suspected SM cases where initial tests are negative. “Our results re-emphasize the implications of KIT mutations for diagnostic comprehensiveness and potential therapeutic strategies (e.g. beyond D816V-specific TK inhibition) and point out the necessity of further studies to elucidate the clinical impact of rare KIT variants,” the authors concluded.
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