Kędzia Małgorzata, Wender-Ożegowska Ewa, Dąbrowska Justyna, Jagodziński Paweł P, Mostowska Adrianna
Department of Reproduction, Chair of Reproduction and Perinatal Medicine, Poznan University of Medical Sciences, 60-535 Poznan, Poland.
Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 60-781 Poznan, Poland.
J Clin Med. 2025 Aug 8;14(16):5618. doi: 10.3390/jcm14165618.
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder with a multifactorial pathogenesis and a well-established genetic component. While pathogenic variants in genes such as and are implicated in a subset of cases, many remain genetically unexplained. This study aimed to investigate the genetic background of ICP in a multi-generational family with recurrent hepatobiliary disease. Whole-exome sequencing was performed on the proband and five female relatives. Variant filtering prioritized rare, exonic or splice-site variants predicted to undergo damage by tools and which were present in all affected family members. Identified variants were assessed using population databases and compared with a control group of 433 unrelated women with uncomplicated pregnancies. Variant confirmation was performed using Sanger sequencing and high-resolution melting analysis. No pathogenic variants were identified in known ICP-associated genes. However, a rare heterozygous missense variant in (c.1610G>A; p.Arg537His; rs779950110) was found in all affected individuals and two younger female relatives. This variant is exceedingly rare in population databases, absent in controls, and predicted to be pathogenic by multiple algorithms. , although not previously linked to ICP, is an ATP-binding cassette transporter expressed in various tissues, including liver compartments. This study reports a novel variant segregating with ICP and early-onset hepatobiliary disease in a family. These findings suggest as a potential new susceptibility gene in ICP, warranting further functional investigation.
妊娠期肝内胆汁淤积症（ICP）是一种特定于妊娠的肝脏疾病，其发病机制具有多因素性且存在明确的遗传成分。虽然诸如[基因名称]等基因中的致病变异在一部分病例中有所涉及，但许多病例的遗传原因仍未得到解释。本研究旨在调查一个患有复发性肝胆疾病的多代家族中ICP的遗传背景。对先证者和五名女性亲属进行了全外显子组测序。变异筛选优先考虑预测会被[工具名称]工具判定为有害的罕见、外显子或剪接位点变异，且这些变异存在于所有受影响的家庭成员中。使用人群数据库评估已识别的变异，并与433名无并发症妊娠的无关女性组成的对照组进行比较。使用桑格测序和高分辨率熔解分析进行变异确认。在已知的与ICP相关的基因中未发现致病变异。然而，在所有受影响个体和两名年轻女性亲属中发现了[基因名称]中的一种罕见杂合错义变异（c.1610G>A；p.Arg537His；rs779950110）。该变异在人群数据库中极为罕见，在对照组中不存在，并且通过多种算法预测为致病性变异。[基因名称]虽然以前未与ICP相关联，但它是一种在包括肝区在内的各种组织中表达的ATP结合盒转运蛋白。本研究报告了一个家族中与ICP和早发性肝胆疾病共分离的一种新的[基因名称]变异。这些发现表明[基因名称]是ICP中一个潜在的新的易感基因，值得进一步进行功能研究。
