A Heterozygous Mutation in the BLM Gene Identified in a Pediatric Patient with an Inborn Error of Immunity

Bloom syndrome is an autosomal recessive disease caused by loss-of-function mutations in the BLM gene. Mutations in this gene cause deformations in the DNA helicase protein, which is functional in DNA repair. DNA repair is known to have an important role in the development of antigen receptors on B and T cells; therefore, DNA repair disturbances may lead to immunodeficiency. However, the cause of immunodeficiency in Bloom syndrome is still undergoing investigation. This case involves a one-year-old with an inborn error of immunity which was associated with a heterozygous mutation in the BLM gene. This patient presented with recurrent infections, febrile seizures, and failure to meet developmental milestones. He was found to have CD8 deficiency and eosinophilic gastroenteritis, prompting further investigation. Lymphocyte enumeration included CD3 (54%), CD3 absolute (2,576), CD3+CD4+ (41%), CD3+CD4+ absolute (1,956), CD3+CD8+ (10%) (low), CD3+CD8+ absolute (477) (low), CD4/CD8 ratio (4.10) (high), CD3+CD4-CD8- (2%), CD3-CD16+CD56+ (11%), CD3-CD16+CD56+ absolute (525), CD19 (35%), and CD19 absolute (1,670). IgG, IgA, and IgM were within normal limits. Genetic testing of 429 genes depicted a heterozygous mutation in the BLM gene (c.2193+1_2193+9del). Poor antibody response to primary polysaccharide vaccines was noted, and this patient was instructed to receive gamma globulin subcutaneously. The mutation causes a disruption of a splice site in intron 9 of the BLM gene. This results in exon 9 being skipped, and the development of a premature termination codon causes nonsense-mediated mRNA decay. The protein encoded by the BLM gene is an ATP and Mg2+-dependent DNA helicase that works to correct DNA when it is damaged and helps regulate any problems that may occur at the replication fork. Cellularly, patients with Bloom syndrome develop breaks in the chromosome, a high sister chromatid exchange, a slower replication fork due to the activation of the ATM–Chk2–γH2AX pathway, increased blockages of replication forks and anaphase bridges, and additional micronuclei in cells. Further studies will need to be conducted to understand the true ramifications of Bloom syndrome on immunodeficiency in children.