DBR1 Gene Mutation: Pathogenicity in the Homozygous State and Its Phenotype in Two Siblings

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• The RNA lariat debranching enzyme (DBR1) is crucial for RNA processing, specifically hydrolyzing 2'-5' branched phosphodiester bonds in lariat introns.
• Defects in DBR1 can lead to the accumulation of lariat introns, causing cellular dysfunction and potentially severe genetic disorders.

Purpose of the Study:

• To investigate the clinical manifestations and genetic basis of a rare genetic disorder caused by DBR1 mutations.
• To characterize the pathogenicity of a specific homozygous DBR1 variant (c.200A>G p.(Tyr67Cys)) in affected siblings.

Main Methods:

• Case study of two siblings with homozygous DBR1 mutations.
• Clinical examination and phenotypic analysis.
• Genetic variant identification and pathogenicity assessment.

Main Results:

• Both siblings presented with a consistent set of severe phenotypes including intrauterine growth restriction, ichthyosis, encephalopathy, respiratory issues, and early mortality.
• Novel phenotypes such as laryngomalacia, hypotonia, elevated intracranial pressure, and hypospadias were observed.
• The homozygous mutation was confirmed as pathogenic, contrasting with a healthy heterozygous sibling.

Conclusions:

• The homozygous mutation in DBR1 (c.200A>G p.(Tyr67Cys)) is pathogenic and leads to a severe, multi-system disorder with a recognizable pattern of phenotypes.
• This study expands the known clinical spectrum associated with DBR1 deficiency, including novel findings and increased susceptibility to respiratory infections.
• The findings underscore the critical role of DBR1 in human development and disease prevention.