Clinical and genetic analysis of a family affected by congenital bile acid synthesis disorder type 2 caused by complex heterozygous variation of AKR1D1 gene

WU Ying; WANG Mei; HONG Zhidan; LI Guigui; ZHANG Ming

doi:10.14188/j.1671-8852.2024.0101

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Clinical and genetic analysis of a family affected by congenital bile acid synthesis disorder type 2 caused by complex heterozygous variation of AKR1D1 gene

更新时间：2026-11-05

- Clinical and genetic analysis of a family affected by congenital bile acid synthesis disorder type 2 caused by complex heterozygous variation of AKR1D1 gene
- Medical Journal of Wuhan University Vol. 46, Issue 6, Pages: 799-805(2025)
- 作者机构：
  
  武汉大学中南医院生殖医学中心湖北武汉 430071
- 作者简介：
- 基金信息：
- DOI：10.14188/j.1671-8852.2024.0101
  CLC： R394.1
- Received：11 February 2024，
  
  Published：25 June 2025
- 稿件说明：
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吴颖,王梅,洪志丹等.AKR1D1基因复合杂合变异所致先天性胆汁酸合成障碍2型一个家系的临床及遗传学分析[J].武汉大学学报（医学版）,2025,46(06):799-805.

WU Ying,WANG Mei,HONG Zhidan,et al.Clinical and genetic analysis of a family affected by congenital bile acid synthesis disorder type 2 caused by complex heterozygous variation of AKR1D1 gene[J].Medical Journal of Wuhan University,2025,46(06):799-805.
吴颖,王梅,洪志丹等.AKR1D1基因复合杂合变异所致先天性胆汁酸合成障碍2型一个家系的临床及遗传学分析[J].武汉大学学报（医学版）,2025,46(06):799-805. DOI： 10.14188/j.1671-8852.2024.0101.

WU Ying,WANG Mei,HONG Zhidan,et al.Clinical and genetic analysis of a family affected by congenital bile acid synthesis disorder type 2 caused by complex heterozygous variation of AKR1D1 gene[J].Medical Journal of Wuhan University,2025,46(06):799-805. DOI： 10.14188/j.1671-8852.2024.0101.

摘要

目的

探讨一例AKR1D1基因变异导致的先天性胆汁酸合成障碍2型家系的临床表现及遗传学特征，为家系的遗传咨询和变异携带者的助孕策略提供指导。

方法

选择2023年7月因“先天性胆汁酸合成障碍患儿生育史”而就诊于武汉大学中南医院的一个家系，收集其临床资料，对患儿先证者及其父母外周血进行全外显子测序，先证者进行遗传学变异检测，利用Sanger测序对其家系成员验证相关基因变异位点，并对变异位点的氨基酸保守性及变异对蛋白质功能的影响进行生物信息学分析。根据美国医学遗传学与基因组协会基因变异解读标准和指南(ACMG)对变异位点进行致病性评级。

结果

全外显子测序结果提示先证者AKR1D1基因存在父源c.580⁃13T>A和母源c.78C>A (p.Tyr26*)复合杂合变异，且c.78C>A (p.Tyr26*)为未见报道的新变异。生物信息学软件预测两位点变异均为有害变异，且在不同物种中高度保守。根据ACMG指南，AKR1D1 c.78C>A (p.Tyr26*)和c.580⁃13T>A均被评为致病变异（PVS1+PM2+PM3+PP4；PS3+PM2+PM3_Strong +PP4），并可为后续的生育方式及生殖遗传阻断提供指导。

结论

AKR1D1

c.78C

A (p.Tyr26*)；c.580⁃13T

A新复合杂合致病变异可能是先证者的致病原因。上述发现丰富了CBAS2的变异谱，并为该家系的诊断、遗传咨询和助孕策略提供了指导和帮助。

Abstract

Objectives

To explore the clinical and genetic features of a family affected by congenital bile acid synthesis disorder type 2 caused by AKR1D1 gene variation

and to provide genetic counseling for the family and the assisted reproductive strategy for the mutation carrier.

Methods

A family was selected from Zhongnan Hospital of Wuhan University in July 2023 due to "fertility history of children with congenital bile acid synthesis disorder". Clinical data were collected

and peripheral blood samples were collected from the patient and his parents. Whole⁃exome sequencing was used to detect genetic variants in the proband

and Sanger sequencing was used to verify related gene variants in family members. The conservation of amino acids and the effects of variations on protein function were analyzed using bioinformatics. The pathogenicity of the variants was evaluated according to the American College of Medical Genetics and Genomics (ACMG) variant interpretation standards and guidelines.

Results

Whole⁃exome sequencing showed that the proband carried compound heterozygous mutations of the AKR1D1 gene

c.580⁃13T>A from his father and c.78C>A (p.Tyr26*) from his mother

and c.78C>A (p.Tyr26*) was a novel variant. Bioinformatics software to predict both variants for harmful mutations

and highly conserved across different species. According to ACMG guidelines

78C>A (p. Tyr26*) and c. 580⁃13T>A of AKR1D1 were both rated as pathogenic variants (PVS1+PM2+PM3+PP4; PS3+PM2+PM3_Strong+PP4)

and can guide the subsequent reproductive mode and reproductive genetic block.

Conclusion

AKR1D1 c.78C>A (p.Tyr26*). A novel compound heterozygous variant c.580⁃13T>A probably underlay the disease in the proband. These findings enrich the mutation spectrum of CBAS2

and provide guidance and help for the diagnosis

genetic counseling and assisted pregnancy strategy of this family.

关键词

Keywords

references

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