Background

Peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders that affect multiple organ systems. Approximately 80% of PBD patients are classifiedin the Zellweger syndrome spectrum, which is generally caused by mutations in the PEX1, PEX6, PEX10, PEX12, or PEX26 genes.

Methods

We present the clinical characteristics of three male members with cholestatic hepatopathy and developmental delay. Next-Generation Sequencing (NGS) was used to analyze 52 genes responsible for hereditary diseases with cholestasis. The variant was confirmed by Sanger sequencing. Dried blood spot (DBS) samples of 537 newborns from Dagestan were tested for the presence of that mutation. The frequency of the mutant allele in the population of Dagestan wasestimated using the Hardy–Weinberg equilibrium.

Results

Symptoms of disease manifested from the first months of life as severe hepatic dysfunction and developmental delay. Physical examination showed jaundice, hepatosplenomegaly, coagulopathy, and normal or slightly elevated level of gamma-glutamyltransferase (GGT), similar to progressive familial intrahepatic cholestasis. The level of C26 and ratio of C26/C22 in plasma were increased. A nucleotide variant in the PEX26 gene was identified: NM_017929.6:c.347 T>A, p.(Leu116Gln) in a homozygous state. Parents and healthy siblings were heterozygous for the mutant allele. This variant was not described in the Database of Single Nucleotide Polymorphism (dbSNP), it is not registered in the Human Gene Mutation Database (HGMD) v. 2020.1. The frequency of the mutant allele in the population of Dagestan is estimated to be less than 0.000931 (99% CI, 0.000929–0.000934).

Conclusions

Our clinical cases from Dagestan describe the phenotype associated with the c.347 T>A,p.(Leu116Gln), variant in the PEX26 gene. We show that the onset of the clinical picture in patients with Zellweger syndrome spectrum could start with severe hepatic dysfunction and cholestasis. We suggest that biochemical screening of PBD in infants with cholestasis is necessary.

中文翻译：

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来自达吉斯坦的一个家族中 PEX26 基因的新突变，其成员受齐薇格谱系障碍的影响

背景

过氧化物酶体生物发生障碍 (PBD) 是一组异质性常染色体隐性遗传疾病，影响多个器官系统。大约 80% 的 PBD 患者属于 Zellweger 综合征谱系，这通常是由PEX1、PEX6、PEX10、PEX12或PEX26基因的突变引起的。

方法

我们介绍了三名患有胆汁淤积性肝病和发育迟缓的男性成员的临床特征。下一代测序 (NGS) 用于分析 52 个与胆汁淤积的遗传性疾病有关的基因。Sanger测序证实了该变体。对来自达吉斯坦的 537 名新生儿的干血斑 (DBS) 样本进行了测试，以确定是否存在该突变。使用 Hardy-Weinberg 平衡估计达吉斯坦人群中突变等位基因的频率。

结果

疾病的症状从生命的最初几个月就表现为严重的肝功能障碍和发育迟缓。体格检查显示黄疸、肝脾肿大、凝血功能障碍、γ-谷氨酰转移酶（GGT）正常或轻度升高，类似于进行性家族性肝内胆汁淤积。血浆中C26水平和C26/C22比值升高。PEX26中的核苷酸变体基因被鉴定：NM_017929.6:c.347 T>A, p.(Leu116Gln) 处于纯合状态。父母和健康的兄弟姐妹是突变等位基因的杂合子。该变体未在单核苷酸多态性数据库 (dbSNP) 中描述，未在人类基因突变数据库 (HGMD) v. 2020.1 中注册。达吉斯坦人群中突变等位基因的频率估计小于 0.000931（99% CI，0.000929–0.000934）。

结论

我们来自达吉斯坦的临床病例描述了与PEX26基因变异体 c.347 T>A,p.(Leu116Gln) 相关的表型。我们表明，齐薇格综合征患者的临床表现可能始于严重的肝功能障碍和胆汁淤积。我们建议对胆汁淤积婴儿的PBD进行生化筛查是必要的。