KNG1 – congenital high-molecular-weight kininogen deficiency

High-molecular-weight kininogen deficiency is an autosomal recessive disorder caused by biallelic loss-of-function variants in KNG1, leading to markedly reduced HMWK activity and isolated prolonged activated partial thromboplastin time in affected individuals. Clinical penetrance appears limited to laboratory coagulopathy without spontaneous bleeding, though rare thrombotic events such as splenic infarction have been documented.

The first molecular report described a Japanese proband with HMWK activity of 0.9% carrying a homozygous c.523_524dupTC (p.Ser175SerfsTer183) frameshift in exon 4, with three heterozygous offspring demonstrating intermediate HMWK reduction ([PMID:24492696]). Shortly thereafter, a Chinese kindred was characterized in which a 67-year-old index case and two younger sisters exhibited severe HMWK deficiency (T (p.Gln486Ter) nonsense variant ([PMID:32185598]).

In 1999, three Japanese patients with total kininogen deficiency were analyzed, and two harbored a c.22C>T (p.Arg8Ter) truncating mutation in exon 5, underscoring recurrent loss-of-function alleles in this population ([PMID:10071463]). More recently, a systematic review and novel genotyping identified 48 severe HMWK deficiency cases across 41 families worldwide, involving ten truncating KNG1 variants including splice-site and nonsense mutations (e.g., c.718C>T (p.Arg240Ter), c.586C>T (p.Arg196Ter), c.306+2T>A) ([PMID:36700498]).

All reported pathogenic alleles are predicted or demonstrated to abrogate protein function, consistent with an autosomal recessive inheritance mode. Segregation in multiple pedigrees confirms that heterozygous carriers are asymptomatic or exhibit mild laboratory abnormalities, while homozygotes or compound heterozygotes manifest profound HMWK deficiency and isolated aPTT prolongation.

Functional assays have delineated critical binding interfaces in the D6 domain of HMWK for prekallikrein and factor XI. Alanine-scanning mutagenesis and surface-induced clotting assays showed that HK variants defective in FXI-binding fail to correct aPTT in HK-deficient plasma, and Kng1–/– mice exhibit impaired arterial thrombosis reversible only by HK capable of mouse FXI interaction ([PMID:37813198]).

Collectively, the genetic, segregation, and functional data constitute definitive evidence that biallelic KNG1 loss-of-function variants underlie congenital high-molecular-weight kininogen deficiency. Recognition of this diagnosis in patients with isolated prolonged aPTT permits accurate genetic counseling, avoids misdiagnosis, and informs evaluation of contact activation-related thrombotic risk.

Key Take-home: Biallelic truncating KNG1 variants cause a laboratory-defined coagulopathy with minimal clinical bleeding, mandating targeted genetic testing in isolated aPTT prolongation.

References

• Internal medicine (Tokyo, Japan) • 2014 • A novel frameshift mutation in exon 4 causing a deficiency of high-molecular-weight kininogen in a patient with splenic infarction. PMID:24492696
• Journal of thrombosis and thrombolysis • 2020 • Severe high-molecular-weight kininogen deficiency due to a homozygous c.1456C–T nonsense variant in a large Chinese family. PMID:32185598
• Journal of thrombosis and haemostasis : JTH • 2023 • Severe high-molecular-weight kininogen deficiency: clinical characteristics, deficiency-causing KNG1 variants, and estimated prevalence. PMID:36700498
• Journal of thrombosis and haemostasis : JTH • 2024 • High molecular weight kininogen interactions with the homologs prekallikrein and factor XI: importance to surface-induced coagulation. PMID:37813198

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