Analysis of two consanguineous Chinese pedigrees affected with Hereditary prokallikrein deficiency and High molecular weight kininogen deficiency
10.3760/cma.j.cn511374-20230901-00105
- VernacularTitle:近亲婚配分别导致遗传性激肽释放酶原和高分子量激肽原缺陷症2个家系的遗传学分析
- Author:
Bile CHEN
1
;
Zuoting XIE
;
Zhou ZHENG
;
Yuan CHEN
;
Huilin CHEN
;
Mingshan WANG
;
Yanhui JIN
Author Information
1. 温州医科大学附属第一医院输血科，温州 325015
- Keywords:
Prokallikrein deficiency;
High molecular weight kininogen deficiency;
KNG1 gene;
KLKB1 gene
- From:
Chinese Journal of Medical Genetics
2024;41(9):1066-1071
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To analyze the genetic variants of two consanguineous Chinese pedigrees affected with Hereditary prokallikrein (PK) and High molecular weight kininogen (HMWK) deficiency and explore their molecular pathogenesis.Methods:A PK deficiency pedigree (10 individuals from 4 generations) and a HMWK deficiency pedigree (6 individuals from 3 generations) which were admitted to the First Affiliated Hospital of Wenzhou Medical University on December 3, 2021 and June 16, 2022, respectively were selected as the study subjects. Clinical data of the two pedigrees were collected, and the related coagulation indexes of the probands and their family members were determined. Genomic DNA of the two pedigrees was extracted from peripheral blood samples. This study was approved by the First Affiliated Hospital of Wenzhou Medical University (Ethics No. KY2022-R193).Results:The plasma PK activity of proband A, a 29-year-old female, and her brother were extremely low (< 1.0%). Proband B was a 66-year-old male with extremely low plasma HMWK activity (< 1.0%). Genetic sequencing revealed that the proband A and her brother had both harbored a homozygous c. 417_418insCATTCTTA (p.Arg140Hisfs*3) insertional variant in exon 5 of the KLKB1 gene, with her grandmother, maternal grandmother, father, mother, sister and son all carrying heterozygous insertion variant, and her ancestor father and husband are both wild-type. Proband B had harbored a homozygous c. 460C>A (p.Pro154Thr) missense variant in exon 4 of the KNG1 gene, and his son carries a heterozygous missense variant. All other members of the pedigree are wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were respectively rated as pathogenic (PVS1+ PM2_Supporting+ PM4) and likely pathogenic (PS4+ PM2_Supporting+ PP3+ PP4). Conclusion:The c. 417_418insCATTCTTA (p.Arg140Hisfs*3) variant of the KLKB1 gene and the c. 460C>A (p.Pro154Thr) variant of the KNG1 gene probably underlay the decreased PK and HMWK activities in the two pedigrees, respectively.
