Q1-8: Disease Assessment at Diagnosis

Question 1: What was the date of diagnosis of Immune Deficiency (ID)?

Immune Deficiencies are characterized by multiple clinical, laboratory, and genetic features. Definitive diagnosis is often based on molecular testing such as detection of mutations in IL-2RG for common gamma chain deficiency (X-linked SCID) or ADA for adenosine deaminase (ADA) deficiency. Report the date the specimen was collected for molecular analysis.

If molecular analysis was not performed, but diagnosis of the recipient with ID was based on newborn screening, report the date of the newborn screening sample collection.

If the recipient had a strong family history of the disease and was tested in utero, the date of birth should be used as the date of diagnosis.

Questions 2-4: What is the immune deficiency molecular abnormality?

A variety of molecular abnormalities have been identified in those with immune deficiencies. Indicate the molecular abnormality used to diagnose the recipient’s immune deficiency.

If the recipient was diagnosed with Omenn Syndrome, indicate the identified molecular abnormality in question 3.

If the recipient has an identified molecular abnormality other than those listed, indicate the other molecular abnormality in question 4.

Table 1. Immunodeficiencies¹²

Disease	Circulating T cells	Circulating B cells	Molecular Abnormality	Inheritance
Common gamma chain (γc; CD132) deficiency May also be referred to as IL2RG deficiency or X-linked SCID	Markedly decreased	Normal or increased	Mutation in IL-2RG	X-Linked
Adenosine deaminase (ADA) deficiency	Absent from birth or progressive decrease	Absent from birth or progressive decrease	Mutation of ADA	Autosomal Recessive
Janus kinase 3 (JAK3) deficiency	Markedly decreased	Normal or increased	Mutation of JAK3	Autosomal Recessive
Recombination-activating gene 1 (RAG1) deficiency	Markedly decreased	Markedly decreased	Mutation of RAG1	Autosomal Recessive
Recombination-activating gene 2 (RAG2) deficiency	Markedly decreased	Markedly decreased	Mutation of RAG2	Autosomal Recessive
IL-7Rα deficiency	Markedly decreased	Normal or increased	Mutation of IL7RA	Autosomal Recessive
DNA cross-link repair 1C (DCLRE1C) / Artemis deficiency	Markedly decreased	Markedly decreased	Mutation of DCLRE1C/ARTEMIS	Autosomal Recessive
CD3γ (gamma) deficiency	Normal (reduced TCR expression)	Normal	Mutation of CD3G	Autosomal Recessive
CD3δ (delta) deficiency	Markedly decreased	Normal	Mutation of CD3D	Autosomal Recessive
CD3ε (epsilon) deficiency	Markedly decreased	Normal	Mutation of CD3E	Autosomal Recessive
CD3ζ (zeta)-chain deficiency	Markedly decreased	Norma	l Mutation of CD3Z	Autosomal Recessive
Zeta-chain (TCR) associated protein kinase 70 dKa (ZAP-70) deficiency	Decreased CD8, normal CD4	Normal	Mutation in ZAP70	Autosomal Recessive
CD25 deficiency	Normal to decreased	Normal	Mutation in IL-2RA	Autosomal Recessive
CD45 deficiency	Markedly decreased	Normal	Mutation of PTPRC	Autosomal Recessive
Purine nucleoside phosphorylase (PNP) deficiency	Progressive Decrease	Normal	Mutation of PNP	Autosomal Recessive
Cernunnos-XLF / NHEJ1 deficiency	Decreased	Decreased	Mutation in NHEJ1/Cernunnos	Autosomal Recessive
DNA ligase 4 deficiency	Decreased	Decreased	Mutation in LIG4	Autosomal Recessive
DNA-protein kinase catalytic subunit (DNA-PKcs) deficiency	Markedly decreased	Markedly Decreased	Mutation of PRKDC	Autosomal Recessive
Adenylate kinase 2 (AK2) deficiency (reticular dysgenesis)	Markedly Decreased	Decreased or normal	Mutation of AK2	Autosomal Recessive
Omenn syndrome	Present; restricted T-cell repertoire, and impaired function	Normal or decreased	Mutation(s) in RAG1, RAG2, ARTEMIS, IL7RA, RMRP, ADA, LIG4, IL2RG, AK2. Some cases have no defined gene mutation
Bare lymphocyte syndrome (MHC class II) deficiency	Normal number, decreased CD4 cells	Normal	Mutation in CIITA, RFX5, RFXAP, RFXANK transcription factors	Autosomal Recessive
Cartilage-hair hypoplasia (CHH) / metaphyseal dysplasia, McKusick type	Varies from severely decreased to normal; impaired lymphocyte proliferation	Normal	Mutations in RMRP	Autosomal Recessive
Orai1 deficiency May also be referred to as Ca++ channel deficiency (orai1 defect)	Normal number, but defective TCR-mediated activation	Normal	Mutation in ORAI1	Autosomal Recessive

¹ Adapted from: International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies. “Primary immunodeficiencies: 2009 update” The Journal of Allergy and Clinical Immunology Volume 124, Issue 6 , Pages 1161-1178, December 2009.

² Al-Herz, W., Bousfiha, A., Casanova, J. L., Chapel, H., Conley, M. E., Cunningham-Rundles, C., … & Tang, M. L. (2011). Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Frontiers in immunology, 2.

Question 5: Is the mutated protein or enzyme expressed?

Immune Deficiency proteins or enzymes may be detected using tests such as Western blotting or an enzyme-linked immunosorbent assay (ELISA). Indicate whether the mutated protein or enzyme was expressed. If the protein or enzyme was expressed, select “yes.” If the protein or enzyme was not expressed, select “no.” If the test was not performed or the results of the test were inconclusive, select “unknown.”

Question 6: What is the pattern of inheritance for the genetic disorder?

Report the pattern of inheritance for the genetic disorder.

Sporadic inheritance indicates that there is no family history of the disease.

X-linked inheritance indicates that the genetic disease is located on the X chromosome and that the lack of a functioning copy of the gene causes the disease. Diseases inherited in an X-linked fashion are passed from parent to child via the X chromosome, a sex chromosome. X-linked disorders are much more common in males (XY) than females (XX) because only one copy of a mutation on the X chromosome is sufficient to cause the disorder in males, whereas females would require that the mutation is present on both X chromosomes to cause the disorder. X-linked SCID, or common gamma chain (γc; CD132) deficiency, is caused by a mutation in the IL2RG gene located on the chromosome X and is the most common type of primary immune deficiency. A second example of a disorder with X-linked inheritance is CD40 ligand deficiency¹.

Autosomal recessive inheritance indicates that two non-functioning copies of the gene are required to cause the disease. In the majority of cases, the mutations for the genetic disease were passed from both parents to the child. Autosomes are non-sex chromosomes numbered 1-22. Because the disorder is recessive, mutations must be present on each chromosome in the pair (i.e., the mutation must be present on the maternal and paternal chromosome) for the disease to be expressed. For example, ADA deficiency (or ADA-SCID) is an autosomal recessive disease caused by mutations in the q13.12 location of the maternally- and paternally -inherited copies of chromosome 20.

If the inheritance pattern was autosomal dominant, leave the question blank and override the error.

Indicate the pattern of inheritance. If the pattern of inheritance is not known, select “unknown” and continue with question 7.

¹ International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies. “Primary immunodeficiencies: 2009 update” The Journal of Allergy and Clinical Immunology Volume 124, Issue 6 , Pages 1161-1178, December 2009.

Question 7: Are the parents of the patient consanguineous (related by blood ancestry)?

Indicate if the recipient’s parents are related by blood ancestry. For example, if the parents of the recipient are first cousins (i.e., the parents are children of two siblings), the relationship is considered consanguineous. The limit for consanguinity is biological parents who are second cousins or less (Bittles A, Clin Genet 2001; 60; 89-98).

Question 8: Are there other blood relatives in the patient’s family with immunodeficiency disease?

Indicate if the recipient has blood relatives that have an immunodeficiency. Blood relatives include parents, siblings, grandparents, cousins, aunts, uncles, and other biological members of the recipient’s extended family, through great-grandparents.

Section Updates:

Question Number	Date of Change	Add/Remove/Modify	Description	Reasoning (If applicable)
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