A novel mutation in the PEX26 gene in a family from Dagestan with members affected by Zellweger spectrum disorder

Natalia A Semenova; Marina V Kurkina; Andrey V Marakhonov; Elena L Dadali; Natalia N Taran; Tatyana V Strokova

doi:10.1016/j.ymgmr.2021.100754

A novel mutation in the PEX26 gene in a family from Dagestan with members affected by Zellweger spectrum disorder

Mol Genet Metab Rep. 2021 Apr 12:27:100754. doi: 10.1016/j.ymgmr.2021.100754. eCollection 2021 Jun.

Authors

Natalia A Semenova¹, Marina V Kurkina¹, Andrey V Marakhonov¹, Elena L Dadali¹, Natalia N Taran², Tatyana V Strokova²

Affiliations

¹ Research Centre for Medical Genetics, 1 Moskvorechye Street, Moscow 115522, Russian Federation.
² Federal Research Centre of Nutrition and Biotechnology, Kashirskoe shosse, d. 21, Moscow 115446, Russian Federation.

Abstract

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.

Keywords: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; Cholestasis; DBS, dried blood spot; GGT, gamma-glutamyltranspeptidase; Hepatic dysfunction; LDG, lactate dehydrogenase; OMIM, Online Mendelian Inheritance in Man; PBD, peroxisome biogenesis disorders; PEX26 gene; VLCFA, very-long-chain fatty acids; ZSD, Zellweger spectrum disorders; Zellweger syndrome spectrum.