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

The RNA lariat debranching enzyme (DBR1) facilitates the hydrolysis of 2'-5' prime branched phosphodiester bonds. It acts on the bonds at the junction of excised lariat intron RNA, converting them into linear molecules for degradation. Mutations in the gene result in the accumulation of lariat introns, leading to multiple system dysfunction. This case involves two siblings who exhibited a homozygous gene mutation in DBR1, identified as the variant c.200A>G p.(Tyr67Cys). Both showed similar manifestations, including premature birth, intrauterine growth restriction, growth deficiency, ichthyosis, encephalopathy, respiratory symptoms, and death within 12-13 months of life, some of which were reported in the literature. Additionally, they showed novel phenotypes, including laryngomalacia, hypotonia, elevated intracranial pressure, and hypospadias. It is important to state that these siblings had another sibling with a heterozygous form and who is healthy, which supports the pathogenicity of the homozygous state. Adding to the association between this mutation and encephalitis, our patients were found to be additionally susceptible to respiratory tract infections. Although many patients with central nervous system disorders ultimately develop pulmonary infections, this is frequently a consequence of progressive neurological impairment, including compromised airway clearance. This paper enriches the existing literature and emphasizes the pathogenicity of the homozygous form.