Table 2.

Classification of SCID on the basis of pathogenic mechanisms.

Genotype	Function	Phenotype	Locus	Inheritance	Clinical features
Defective survival of haematopoietic precursors
AK2	Regulates the adenine nucleotide composition and catalyses the reversible transfer of phosphate groups	T–B–NK–	1p35.1	AR	Lymphopenia, hypoplasia of secondary lymphoid organs and thymus, multiple infections, profound neutropenia, hearing abnormality, thymic dystrophy
Toxic metabolite accumulation
ADA	Component of the purine salvage pathway. Removes toxic metabolites and prevents inhibition of lymphoid cells	T–B–NK–	20q13.11	AR	Multiple recurrent opportunistic infections, hypoplasia, FTT, skeletal alterations
PNP	Reversibly catalyses the phosphorolysis of purine nucleosides	T–B + NK–	14q11.2	AR	Persistent opportunistic infections, autoimmune disorders
Cytokine signalling anomalies
IL2RG	Required for the activation of JAK3 for intracellular signal transduction	T–B + NK–	Xq13.1	XL	Recurrent multiple opportunistic infections (Pneumocystis jirovecii), failure to thrive, oral candidiasis, absent tonsils and lymph nodes
JAK3	Tyrosine Kinase., essential to differentiate haematopoietic cells	T–B + NK–	19p13.1	AR	Protracted diarrhoea, failure to thrive, life-threatening opportunistic infections
IL7RA	Essential development of T-cell and activation of JAK3 kinase	T–B + NK+	5p13 IL7	AR	Diarrhoea, persistent rotavirus gastroenteritis, weight loss, progressive cough, vomiting, poor appetite, failure to thrive
V(D)J recombination and problems in T-cell receptor
RAG1 or RAG2	Recombinases required for DNA recombination in B and T cell development	T–B–NK+	11p13	AR	Apart from opportunistic infections, patients can also develop fetures of Omenn syndrome (hepatosplenomegaly, lymph node swelling, eczema, eosinophilia, elevated IgE) and granuloma formation
Artemis	DNA repair process during V(D)J recombination	T–B–NK+	10p	AR
DNA PKcs	Repair of double-stranded DNA breaks and in the process of recombination	T–B–NK+	8q11.21	AR	Recurrent oral candidiasis, lower respiratory tract infections, failure to thrive, growth failure, microcephaly, and seizures
NHEJI	DNA repair factor involved in the NHEJ pathway	T–B–NK+	2q35	AR	Neural disorders, recurrent bacterial infections, microcephaly, growth retardation, bird-like face, increased radiosensitivity
LIG4	Mediates V(D)J recombination and DSB repair through the NHEJ pathway	T–B–NK+	13q33.3	AR	Microcephaly, facial dysmorphisms, retarded growth, neurological abnormalities, bone marrow failure, pancytopenia
TCR abnormalities
CD45	Protein tyrosine phosphatase essential for signal transduction	T–B + NK+	1q31-q32	AR	Failure to thrive, diarrhoea, oral thrush, pneumonia, disseminated BCG infection
CD3δ	TCR/CD3 complex component, involved in signal transduction	T–B + NK+	11q23.3	AR	Defective T-cell development and signal transduction
CD3ε	Part of TCR-CD3 complex, involved in T-cell development	T–B + NK+	11q23.3	AR	Defective T-cell development, immunodeficiency
CD3ζ	Component of TCR-CD3 complex, important for antigen recognition to different signal-transduction pathways intracellularly	T–B + NK+	1q24.2	AR	Erythroderma, protracted diarrhoea, pulmonary abscess, impaired immune response.
CORO 1A	Cell cycle progression, signal transduction, gene regulation and cell death	T–B–NK+	16p11.2	AR	T cell lymphopenia, susceptibility to infection and immune dysregulation
Thymic abnormalities
FOXNI	Required for thymic epithelial cell development, proliferation and terminal differentiation of TEC sublineages, T cell progenitor growth, and fate determination	T–/lowB + NK+	17q11.2	AR	Hairlessness and athymia, Atrophic thymus, T-cell immunodeficiency, congenital alopecia, nail dystrophy
DiGeorge syndrome	Disorder due to microdeletion of chromosome 22	T–B + NK+	22q11.2	AD/Denovo	Psychiatric disorders, cardiac defects, immunodeficiency, facial malformations, hypocalcaemia, polydactyly