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Genomic Analysis IDs New Gene Related to Immunodeficiency

NEW YORK (GenomeWeb) – An international team led by the Boston Children's Hospital has identified the genetic cause of an immunodeficiency that leads to early-onset, invasive infections associated with a broad array of defects in immunity.

The researchers sequenced the exomes of five unrelated patients from different ethnic backgrounds but with similar clinical phenotypes and also performed linkage analysis and homozygosity mapping.

Publishing their findings this week in the New England Journal of Medicine, they found inactivating mutations to the DOCK2 gene in all five patients, and confirmed via immunoblot analysis of patients' immune cells as well as previous animal and experimental studies that those mutations were causative of the immune deficiency.

"Although congenital immunodeficiencies are rare diseases, the study of these disorders has been essential in identifying key mechanisms governing the immune system's development and function, and how it helps fight against infections," Luigi Notarangelo, an author of the study and professor of pediatrics at Harvard Medical School, said in a statement.

Identifying the genetics involved can enable earlier diagnosis and treatment via a hematopoietic stem cell transplant. Now that the gene is known, babies can be screened as newborns rather than after developing "serious infections, which could lead to death or compromise the efficacy" of a stem cell transplant, Notarangelo added.

Of the five patients, one was born to Lebanese parents, one to Finnish parents, two to Turkish parents, and one to parents from Honduras and Nicaragua. Three were born from consanguineous parents. All had severe recurring infections including pneumonia, bronchitis, respiratory tract infections, meningoencephalitis, and diarrhea, and had immunologic abnormalities consistent with immunodeficiency.

Exome sequencing was performed for all five patients. For those born to consanguineous parents, linkage analysis or homozygosity mapping was also performed. For the patients from consanguineous parents, analysis focused on genes in which there were unreported homozygous variants, and for the patients from nonconsanguineous parents, the researchers focused in on genes with two or more variants.

All five patients harbored biallelic mutations in DOCK2, which were confirmed via Sanger sequencing. Collectively, the team identified seven distinct DOCK2 mutations in the five patients, four of which led to premature termination and three of which were predicted to be deleterious missense mutations.

Next, the team wanted to confirm that inactivation of DOCK2 would lead to immunodeficiency, so they created cell lines from the patients, including a T-cell line from two patients and B cells from another patient. Two patients did not have any biologic specimens. Analysis of the patients' T-cell lines found no to little expression of DOCK2.

Previous studies in mice have shown that DOCK2 plays an important role in the activation of T-cell receptors. And other experimental data has found that DOCK2 has a role in lymphocyte development, immune surveillance of lymph nodes, and the recruitment of immune cells to inflamed sites. Stimulating the T cells collected from patients revealed an impaired immune response.

The researchers also found that DOCK2 was impaired not just in hematopoietic cells, but also nonhematopoietic cells, which potentially also play a role in the pathogenesis of patients' viral infections.

Importantly, three patients received stem cell transplants and returned to normal immunologic function and recovered from their infections, suggesting that not only does DOCK2 have potential diagnostic implications, but also, "correction of hematopoietic cells may be sufficient to rescue the clinical phenotype," the authors wrote. 

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