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A new mutation leading to Zellweger syndrome has been identified at RCMG

Two families with three children with an unspecified diagnosis contacted doctors at the Academician N.P. Bochkov Research Centre for Medical Genetics. Both families came from the southern region. From the first months of their life, all children showed symptoms of a disease in the form of cholestasis, severe liver function abnormalities, developmental delays.

The RCMG geneticists compiled a complete family history and determined that members of both families were related. Exome sequencing revealed a new mutation in the PEX26 gene leading to a rare disease, Zellweger syndrome. The parents and healthy siblings were heterozygous for the mutant allele. The identified mutation was not described in the GnomAD database and is not registered in the Human Gene Mutation Database.

 “The patients turned out to be members of one big family, and the new mutation could be explained by the founder effect”, explained Natalia Semenova, Candidate of med. sci., senior researcher of the RCMG Research and Counselling Department. "We have also analyzed over 500 blood samples from patients originating from the same region to rule out the new mutation being characteristic of this area in general. The study showed that this nucleotide variant, which lead to Zellweger syndrome, was typical only for that family.

The disorders of the central nervous system are deemed the first symptoms of Zellweger syndrome. However, these symptoms are extremely difficult to recognize in newborns. The observation of patients with the new mutation at RCMG has led to the conclusion that the first manifestations of Zellweger syndrome may be severe hepatic dysfunction and cholestasis rather than neurological abnormalities.

 “A new mutation in the PEX26 gene leads to the early development of cirrhosis, while patients may show neurological symptoms later," Natalia Semenova explains. "This is crucial to know in order to differentiate the diagnosis in patients with cholestasis. Zellweger syndrome belongs to a group of diseases whose symptoms are similar to some other forms, including curative forms. At the same time, the approaches to treatment of the diseases are fundamentally different. A quick diagnosis using biochemical methods will help the physician to make a correct diagnosis in a shorter time.”

To specify the diagnosis, it is not necessary to perform a genetic analysis at the first stage, given that this syndrome is genetically heterogeneous and requires multigeneic studies. The first-line analysis, in this case, should be a biochemical analysis of specific blood fatty acid levels.

Semenova NA, Kurkina MV, Marakhonov AV, Dadali EL, Taran NN, Strokova TV. 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. PMID: 33912394; PMCID: PMC8065337.