Defects in genes that produce components of the homologous recombination pathway result in diseases such as Ataxia Telangiectasia, Seckel Syndrome, Nijimegan Breakage Syndrome, and Fanconi Anemia, which are characterized by physical abnormalities with either immunodeficiency and/or predisposition to cancer development. Įukaryotic cells possess two mechanisms by which dsDNA breaks are repaired: homologous recombination (HR) and non-homologous end joining (NHEJ). However, once the dsDNA breaks are created by the RAG complex, proper repair must take place in order to avoid a differentiation arrest, which in B cells occurs at the transition from cytoplasmic Igμ negative to Igμ positive pre-B cells, and in T cells occurs at the transition from pro-T to double negative pro-T cells. ![]() Defects in RAG also produce a T-B- form of SCID, but without radiosensitivity. The first step in V(D)J recombination involves creation of double-stranded DNA (dsDNA) breaks and subsequent hairpin formation by an enzymatic complex produced by the Recombination Activating genes (RAG) 1 and 2 ( Figure 1). A variety of genetic mutations have now been linked to the T-B- phenotype, most of which result in defects in the protein machinery required for the V(D)J recombination events critical for producing the diverse repertoire of the T- and B-cell immune system. The T-B- phenotype accounts for approximately 30% of SCID patients and is associated with worse outcomes following hematopoietic cell transplantation (HCT) in most, but not all studies. Severe Combined Immunodeficiency Disease (SCID) has classically been divided into those patients with residual B cells (T-B+ phenotype) and those whose defects produce an absence of both T cells and B cells (T-B- phenotype). Significantly more research needs to be done in order to determine the long-term outcomes of radiosensitive SCID patients following HCT, as well as to discover novel non-toxic approaches to HCT that might benefit those with intrinsic radio- and chemo-sensitivity, as well as potentially all patients undergoing an HCT. Because of their sensitivity to certain forms of chemotherapy, the approach to donor selection and type of conditioning regimen utilized for a radiosensitive SCID patient requires careful consideration. Known etiologies of radiosensitive SCID include deficiencies of Artemis, DNA Ligase IV, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and Cernunnos-XLF, all of which have been treated with HCT. Patients with the radiosensitive form of SCID may also have increased short- and long-term sensitivity to the alkylator-based chemotherapy regimens traditionally utilized for conditioning prior to allogeneic hematopoietic cell transplantation (HCT). NSIRA and the Office of the Privacy Commissioner of Canada jointly conducted a review of 2020 disclosures.Inherited defects in components of the non-homologous end joining DNA repair mechanism produce a T-B-NK+ severe combined immunodeficiency disease (SCID) characterized by heightened sensitivity to ionizing radiation. The National Security and Intelligence Review Agency ( NSIRA) conducted a review of 2019 disclosures under SCIDA. ![]() The National Security and Intelligence Review Agency Act established an independent review function of SCIDA. ![]() SCIDA permits disclosures where the disclosing institution satisfies itself that the information will contribute to the exercise of the recipient institution’s jurisdiction or responsibilities in respect of activities that undermine the security of Canada, and will not affect any person’s privacy interest more than is reasonably necessary (the disclosure test). SCIDA seeks to strike a reasonable balance between privacy and national security. SCIDA authorizes institutions to disclose information relevant to national security, including personal information, to a select group of federal government institutions with national security mandates.Īn important concern in the development of SCIDA was risk to law-abiding citizens that comes when the personal information of many is shared to identify the few individuals actually involved in activities of concern to national security. The Security of Canada Information Disclosure Act ( SCIDA) was adopted in 2019 after much parliamentary debate with an aim to enable more timely and effective information sharing across government for national security purposes.
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