Clinical phenotype and genetic analysis of progressive familial intrahepatic cholestasis type 8 caused by KIF12 gene compound heterozygous variation
10.3760/cma.j.cn511374-20241203-00632
- VernacularTitle:KIF12基因复合杂合变异所致进行性家族性肝内胆汁淤积症8型1例患儿的临床表型及遗传学分析
- Author:
Xiaoying ZHOU
1
;
Jun ZHANG
;
Wenting ZHANG
Author Information
1. 南通大学附属常州儿童医院儿科中心实验室，常州 213003
- Publication Type:Journal Article
- Keywords:
KIF12 gene;
Progressive familial intrahepatic cholestasis 8;
Compound heterozygous variants
- From:
Chinese Journal of Medical Genetics
2025;42(9):1132-1140
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the clinical manifestation and genotype of a child with Progressive familial intrahepatic cholestasis 8 (PFIC8) due to variant of KIF12 gene. Methods:A child diangosed with PFIC8 at Changzhou Children′s Hospital in October 2017 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples (3 mL each) were collected from the patient, her parents and younger sister. Following extraction of genomic DNA, whole exome sequencing (WES) was carried out. Candidate variants were validated using Sanger sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was classified. This study has been approved by the Medical Ethics Committee of Changzhou Children′s Hospital (Ethics No.: 2023-002).Results:The main clinical manifestations of the child included high GGT cholestasis, portal hypertension, splenomegaly, and abnormal liver enzymes. WES revealed that she has harbored compound heterozygous variants of the KIF12 gene, namely c. 245G >A (p.Arg82Gln) and c. 1291del (p.Ser431Valfs*13). Bioinformatics analyses showed that both variants were pathogenic. A total of 25 cases were reported in 7 English literature, including 13 males and 12 females. All patients had presented with high GGT cholestasis. Some had progressed to cirrhosis, and 3 cases also had renal lesions. No death was reported. Six children were treated with LTx. Nineteen children were found to harbor homozygous variants of the KIF12 gene, and the remaining six harbored compound heterozygous variants of the same gene. The most common mutation was c. 655C>T (p.Arg219*). The mutation sites are mainly located in the Kinesin motor catalytic domain, with high GGT cholestasis as the main clinical feature. No correlation was found between the genotype and phenotype. Conclusion:PFIC8 caused by KIF12 deficiency is mainly characterized by high GGT cholestasis, for which there is no effective treatment. The c. 245G>A and c. 1291del compound heterozygous variants of the KIF12 gene probably underlay the pathogenesis in this child.
