In a striking illustration of how a single genetic deletion can disrupt the body’s clotting cascade without ever putting a patient in danger, researchers at The First Affiliated Hospital of Wenzhou Medical University in China have reported a rare case of hereditary high-molecular-weight kininogen deficiency caused by a previously unknown frameshift mutation in the KNG1 gene. The case, published as an open-access report in Annals of Hematology, describes a patient whose blood tests suggested a severe bleeding disorder, yet who exhibited no abnormal bleeding at all. The finding not only expands the known mutational landscape of this enigmatic condition but also carries an urgent practical message for clinicians: an dramatically prolonged clotting time in the laboratory does not always mean a patient is at risk of hemorrhage, and misinterpreting such results can lead to unnecessary, invasive interventions.
The clinical puzzle began with a routine coagulation workup. The patient’s activated partial thromboplastin time, or APTT, one of the most commonly ordered tests in hospital laboratories, was found to be significantly prolonged. APTT measures the efficiency of the intrinsic pathway of coagulation, the branch of the clotting system that depends on a chain of protein factors circulating in plasma. When one link in that chain is missing or defective, the test tube reaction slows dramatically and the reported time lengthens. In most circumstances, a markedly prolonged APTT signals an elevated risk of bleeding and triggers a cascade of further testing, transfusion planning, and, in surgical contexts, potential postponement of procedures. For this patient, however, the laboratory abnormality stood in stark contradiction to the clinical picture, a phenomenon hematologists call genotype-phenotype dissociation.
The Chinese team, led by Fengjiao Wang and corresponding author Lihong Yang of the Department of Laboratory Medicine, pursued the discrepancy systematically. Mixing studies and factor assays pointed away from the classic deficiency states and toward a deficit of high-molecular-weight kininogen, a large plasma protein known as HMWK that serves as a cofactor in the intrinsic pathway. HMWK does not itself possess procoagulant enzymatic activity; instead, it acts as a molecular scaffold, binding to negatively charged surfaces and positioning factor XI and prekallikrein for activation by factor XIIa. Without HMWK, this assembly fails, and the in vitro clotting reaction measured by APTT grinds to a halt. Crucially, however, the in vivo relevance of this pathway to hemostasis has long been questioned, and individuals with complete HMWK deficiency characteristically bleed no more than healthy people, because the extrinsic and tissue factor pathways compensate for the intrinsic defect in real life.
Genetic sequencing provided the definitive answer. The analysis identified a novel homozygous deletion, designated c.628_629delAA, located in exon 5 of the KNG1 gene, which encodes the kininogen precursor protein. The deletion of two adenine bases is a classic frameshift mutation: it shifts the reading frame of the genetic code from that point onward, scrambling every downstream codon. In this case, the frameshift generates the amino acid substitution p.Asn210Phe at the new reading position and then, just fourteen codons later, introduces a premature termination codon, producing the notation fs*15. The result is a truncated protein that lacks the functional domains essential for HMWK’s role in the contact phase of coagulation. Applying the standards of the American College of Medical Genetics and Genomics, the team classified the variant as pathogenic, given its nature as a loss-of-function frameshift in a gene whose biallelic loss produces the observed biochemical phenotype.
The inheritance pattern followed classical autosomal recessive genetics. Because the patient inherited two copies of the mutant allele, one from each parent, essentially no functional HMWK was produced, and APTT values soared. Family screening revealed that heterozygous relatives carrying a single mutant copy had mildly reduced HMWK activity, yet their APTT values remained entirely within the normal range. This dose-effect relationship demonstrates that a single functional KNG1 allele produces enough kininogen to sustain a normal laboratory coagulation profile, while two defective alleles are required to unmask the abnormality. The finding has direct implications for genetic counseling: carriers are asymptomatic and undetectable by routine coagulation testing, so only molecular analysis can identify them, and only molecular analysis of both parents can predict recurrence risk in future pregnancies.
The rarity of the condition adds to its scientific value. Hereditary HMWK deficiency, historically known as Fitzgerald trait after the first described patient, has been reported in only a small number of families worldwide, and each new case contributes to a mutational catalog that remains strikingly short. The novel c.628_629delAA deletion identified in this Chinese patient expands that catalog and illustrates the kind of variant most likely to cause the condition: loss-of-function mutations that truncate the protein before its critical binding domains. Previous reported cases have involved diverse mutations scattered across the gene, consistent with the expectation that many different disruptions of KNG1 can produce the same laboratory phenotype. The Wenzhou case also highlights that the condition may be substantially underdiagnosed, since many affected individuals, being clinically healthy, may never come to medical attention unless an APTT happens to be checked before surgery or during an unrelated evaluation.
The clinical stakes of correct diagnosis are considerable. A prolonged APTT in a preoperative patient conventionally prompts either cancellation of surgery, empirical correction attempts with fresh frozen plasma, or extensive hematologic investigation for hemophilia, von Willebrand disease, lupus anticoagulants, or acquired inhibitors. Each of these pathways carries cost, delay, and in the case of plasma transfusion, genuine risk of transfusion reactions or alloimmunization. Recognizing that isolated APTT prolongation with normal prothrombin time, normal bleeding history, and reduced HMWK activity indicates a benign entity allows clinicians to proceed with appropriate reassurance. The authors of the report emphasize that systematic genetic screening of both patients and their family members is clinically important, not merely for scientific completeness, but because definitive molecular characterization resolves diagnostic uncertainty that biochemical testing alone cannot.
The report also contributes to a broader biological conversation about why the contact pathway exists at all. Decades of research have shown that individuals deficient in factor XII or HMWK do not bleed abnormally, even though their APTT values can be extraordinarily prolonged. This paradox has reshaped thinking in thrombosis research: if the intrinsic pathway is dispensable for preventing bleeding, it may nevertheless be essential for pathological clot formation, and inhibiting contact-phase proteins has become an attractive antithrombotic strategy that could theoretically prevent clots without increasing bleeding risk. Rare patients like this one serve as natural experiments that validate such approaches, demonstrating at the level of human physiology that a lifetime of absent HMWK activity is compatible with normal hemostasis. Epidemiological observations have even suggested that severe HMWK deficiency may protect against venous thromboembolism, adding an intriguing twist to the story of a mutation that leaves its carrier laboratory-abnormal but clinically well.
From a laboratory medicine perspective, the case underscores the importance of a disciplined diagnostic algorithm for unexplained APTT prolongation. The standard sequence begins with mixing studies, which distinguish factor deficiencies, where pooled normal plasma corrects the prolongation, from inhibitors, where it does not. Correction then leads to sequential factor assays through the intrinsic pathway: factors VIII, IX, XI, and XII, followed by the less commonly tested contact proteins, prekallikrein and HMWK. Because HMWK deficiency is so rare, it is often the last possibility considered, and many laboratories lack routine access to kininogen activity assays. The Wenzhou group’s workflow, moving from coagulation phenotyping to targeted sequencing of the KNG1 gene, offers a template other centers can follow. The measurement of profoundly reduced HMWK activity in the proband, alongside mildly reduced activity in heterozygous relatives, illustrates how genotype and biochemical phenotype track together in this condition with unusual precision.
The report, which was peer reviewed and published with a permanent DOI as an early-access article subject to final editorial production, was approved by the ethics committee of The First Affiliated Hospital of Wenzhou Medical University, and the authors declared no competing interests. The work was supported by the Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province and by municipal science and technology funds from Wenzhou. Beyond its immediate value to hematologists and laboratory physicians, the case stands as a vivid reminder that the genome continues to hold explanations for laboratory curiosities that have puzzled clinicians for generations, and that the tool most likely to resolve them, systematic sequencing of patients and their families, has now become fast and affordable enough to be applied whenever a blood test and a bedside picture refuse to agree. For the patient at the center of the report, the conclusion is the most reassuring one possible in coagulation medicine: the frightening numbers on the laboratory report were never a threat to life.
Subject of Research: Hereditary high-molecular-weight kininogen (HMWK) deficiency caused by a novel homozygous frameshift mutation (c.628_629delAA, p.Asn210Phe fs*15) in the KNG1 gene, presenting as prolonged APTT without bleeding.
Subject of Research: Cancer
Article Title: Genetic and clinical phenotype analysis of a case of high-molecular-weight kininogen deficiency caused by a frameshift mutation c.628_629delAA in the KNG1 gene
Article References: Wang, F., Xie, H., Zhou, X., You, L., Wang, M., & Yang, L. (2026). Genetic and clinical phenotype analysis of a case of high-molecular-weight kininogen deficiency caused by a frameshift mutation c.628_629delAA in the KNG1 gene. Annals of Hematology. https://doi.org/10.1007/s00277-026-07204-9
Image Credits: AI Generated
DOI: 10.1007/s00277-026-07204-9
Keywords: High-molecular-weight kininogen deficiency, KNG1 gene, frameshift mutation, c.628_629delAA, APTT prolongation, genotype-phenotype dissociation, autosomal recessive inheritance, intrinsic coagulation pathway, premature termination codon, genetic screening, Annals of Hematology
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Juliet Wilcox. (September 4, 2026). KNG1 frameshift mutation causes high-molecular-weight kininogen deficiency. Scienmag. https://scienmag.com/kng1-frameshift-mutation-causes-high-molecular-weight-kininogen-deficiency/
Juliet Wilcox. “KNG1 frameshift mutation causes high-molecular-weight kininogen deficiency.” Scienmag, 4 September 2026, https://scienmag.com/kng1-frameshift-mutation-causes-high-molecular-weight-kininogen-deficiency/. Accessed 4 September 2026.
Juliet Wilcox. “KNG1 frameshift mutation causes high-molecular-weight kininogen deficiency.” Scienmag. September 4, 2026. https://scienmag.com/kng1-frameshift-mutation-causes-high-molecular-weight-kininogen-deficiency/
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Tags: APTT test interpretationAPTT test significanceblood clotting mechanismsclinical implications of coagulation testscoagulation cascade disruptionframeshift mutationgenetic basis of bleeding disordersgenetic landscape of bleeding disordersGenetic mutation in KNG1 genehereditary bleeding disorderhigh-molecular-weight kininogen deficiencyinvasive interventions risklaboratory diagnostics in hematologyprolonged clotting timerare genetic disorder
