HistoryThis section has been translated automatically.
Bork K et al (2019)
Comment: Knowledge of rare genetic diseases such as hereditary angioedema (HAE) has evolved in parallel with the development of new molecular tools. C1 inhibitor (C1-INH) deficiency has been recognized as the major cause of HAE (HAE-C1-INH) since the 1960s. Discovery of the broad spectrum of mutations affecting the C1-INH gene (SERPING1) was not possible until the late 1980s, when Sanger sequencing became available and more accessible worldwide.
However, the involvement of other genes in HAE was not discovered until 2006 with the description of mutations in the F12 gene in patients with HAE and normal C1-INH. The knowledge gained through the new era of genomics has been crucial for the discovery of mutations in additional genes, improving or explaining the understanding of the complex pathogenesis of this phenotypically largely identical disease. In the last three years, advanced next-generation sequencing techniques have enabled the identification of mutations in five additional novel genes associated with hereditary angioedema variants with normal C1-INH (nC1-INH-HAE): ANGPT1 (angiopoietin-1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin), and HS3ST6 (heparan sulfate glucosamine 3-O-sulfotransferase 6).
DefinitionThis section has been translated automatically.
Hereditary angioedema-6 (HAE6) is an autosomal dominant inherited disorder caused by a heterozygous mutation in the KNG1 gene (612358) on chromosome 3q27.
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Occurrence/EpidemiologyThis section has been translated automatically.
EtiopathogenesisThis section has been translated automatically.
In 6 affected members of a third-generation German family with HAE6, Bork et al. (2019) identified a heterozygous missense mutation in the KNG1 gene (M379K; 612358.0005). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. They were consistent with the clinical situation. It is suggested that the mutation occurs at the cleavage site for the production of bradykinin and may alter this process, possibly leading to the production of a functionally active but aberrant bradykinin. Patients had normal prekallikrein and HMWK antigen and activity levels.
Loules et al (2020) identified a heterozygous missense mutation in the KNG1 gene (P574A; 612358.0006) in three male members of a third-generation Italian family with HAE6. Two patients were heterozygous for a missense variant R487C (c.1459C-T) in the ACE gene (106180), whereas the third patient, who had only one seizure during his lifetime, did not carry the ACE variant. It is suggested that the pathogenicity of the KNG1 variant may depend on the presence of the ACE variant. The results suggest that in some cases HAE is a complex symptom influenced by multiple genes.
Clinical featuresThis section has been translated automatically.
Clinical manifestations of this syndrome include subcutaneous and submucosal swelling episodic in adulthood, most commonly affecting the face, mouth, and tongue. Some patients also observed edema of the distal limbs. Less common are crampy abdominal symptoms. Complement component inhibitor (C1INH; 606860) levels are normal (Bork et al. 2019).
Case report(s)This section has been translated automatically.
Bork et al (2019) reported on a German family with 3 generations in which 6 individuals aged 34 to 81 years had HAE. They were 5 women and 1 man, and the first symptoms appeared between the ages of 17 and 55 years. Five patients had lip or facial swelling, 2 had swelling of the hands or feet, and 2 had abdominal attacks. Tongue swelling occurred in only 1 patient and did not require ventilatory assistance. Shortness of breath was not reported. Triggering factors were pressure and stress in 3 patients. In 1 patient, the symptoms were triggered by taking oral contraceptives. In others, this was not the case. Although C1INH levels and activity were normal, 1 patient responded to treatment with C1INH concentrate.
LiteratureThis section has been translated automatically.
- Bork K et al. (2019) Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin. (Letter) Allergy 74: 2479-2544.
- Loules G et al. (2020) Deciphering the genetics of primary angioedema with normal levels of C1 inhibitor. J Clin Med 9: 3402.
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