Herein, we reported the clinical and molecular features of 4 patients with SCID and 4 patients with atypical SCID. Atypical SCID arises from mutations in the same SCID-causing genes according to the molecular viewpoint, while the clinical presentations differ from typical SCID. Although recurrent pneumonia was the most common clinical manifestation in patients with atypical SCID, immune dysregulations were suggested as a key clue for the diagnosis of this type of SCID [2]. A multicenter cohort study of 285 SCID patients was conducted for nine years in North America (2014), to establish diagnostic criteria for SCID and other related diseases. The importance of genetic studies and their beneficial approach is to define a precise diagnosis of SCID or other related diseases and reduce the possible misdiagnosis that has been made by the immunological evaluations [12].
During three decades of observation on 111 Italian SCID patients, a lack of relevance between genotype and immunophenotype has been noticed in the most patients with atypical SCID [3]. Reported a higher mortality rate, before treatment in patients with atypical SCID compared to those with typical SCID had primarily been due to misdiagnosis and low awareness of this condition [3].
In the current study, 7 novel mutations in RAG2, IL-7R, LAT, ADA, JAK3, LIG4 genes and a reported mutation in RAG1gene were found in eight patients. Patient 1 and 2 with two distinctive novel mutations (I273T and G44X) presented atypical and typical SCID, respectively. RAG2 protein is involved in various biological processes, including B cell differentiation, T cell differentiation in the thymus and T cell lineage commitment, and most variants in this gene is detrimental.
The mutation (c.1331C > T/p.A444V) detected in patient 3 of this study was previously reported in an Italian patient with atypical Omenn syndrome [15]. However, patient 3 harboring the same mutation has not presented autoimmunity and inflammation related to Omenn syndrome.
Patient 4 presented atypical SCID with a frameshift mutation leading to the truncated IL7R protein (F361WfsTer17). Defect in IL7R is a common cause of (T-B + NK+) SCID as IL7R has a crucial role in T cell survival. There is no report of atypical SCID caused by defective IL7R except in one case in a cohort study conducted in The United States and Canada during 2010 to 2018 [9].
LAT deficiency has been found in patient 5 and presented high serum levels of Igs, which is comparable with previously reported LAT deficient patients. The relevance between the linker for activation of T cells (LAT) and T cells has been initially explained by Zhang et al. while studying LAT knockout mice [17]. LAT provides a physical connection between TCR and other downstream signaling molecules involved in T cell maturation and activation [18]. The first report of LAT-deficient human provided by Keller et al. in 3 Arab siblings with CID, immune dysregulation, and severe autoimmune disease [19]. The second report was released by Bacchelli et al. describing a Pakistani family with (T-B + NK+) SCID [20]. The current study could be the third report with a LAT-deficient patient harboring a homozygous mutation in exon 10 ((Tyr207CysfsTer33) of LAT.
ADA deficiency in patient 6 with atypical SCID (T + B-NKlow) was genetically confirmed at thirteen years old, despite having early onset age of the disease. A splice site mutation (c.780 + 1G > A) leading to truncated and non-functional ADA protein has been found in this patient. Unlike the other patients who had FTT in this study, she was over
weighted due to hypothyroidism. Moreover, evident behavioral abnormality and developmental delay were noticed in the patient. Accumulation of dATP results in lymphocytotoxicity in T cells and neurodevelopmental abnormalities (22, 23).
A novel stop gained JAK3 mutation was noticed in patient 7 with T-B + NK- SCID phenotype. Disseminated BCGiosis, viral infections and FTT are common clinical manifestations of JAK3 deficiency [21]. His sister with SCID phenotype and BCGiosis had died at 5 months without a genetic diagnosis. Mutations in JAK3 have been reported in 7–14% of SCID patients [22]. JAK3 is an essential tyrosine kinase for signaling the common γ chain subunit of cytokine receptors, including IL-7R and IL-15R, which are related to T and NK cell development [23].
A novel missense LIG4 mutation was found in patient 8 with typical SCID and T-B-NK + phenotype. LIG4 deficiency is a very rare autosomal immunodeficiency, and about 62 patients with this disorder have been reported since 1990 [24]. LIG4 protein plays roles in the different biological processes, including cell cycle, cell division, DNA repair, and DNA damage. Most LIG4 deficient patients have presented microcephaly, immunodeficiency, developmental delay, pancytopenia, and sensitivity to ionizing radiation. Moreover, facial dysmorphism, short stature, skin conditions and susceptibility to malignancy have been reported in these patients [25]. Clinical manifestations range from severe to moderate, mild and even symptomless [24, 26]. Recently, a patient with LIG4 missense mutation has been reported who had Behçet’s disease (BD)-like phenotype [27]. However, developmental delay and microcephaly were not evident in P8 with the novel LIG4 missense. Furthermore, the result of the TREC assay of this patient showed undetectable levels of TREC, which was in accordance with the immunophenotyping findings of SCID patients [28].
Moreover, structure visualization and mutagenesis analysis showed G428 in LIG4 is located in the linker part of the molecule. Therefore, changing Gly, a flexible amino acid without a side chain to, Arg, may change the protein conformation and its flexibility. On the other hand, G428 is beside metal binding site (E427); which this mutation may interfere with magnesium binding at this position (Fig. 2).
Up to now, the only curative option to restore the immune system in SCID patients is hematopoietic stem cell transplantation (HSCT). Patients 1, 4, and 6 with atypical SCID and patient 8 with typical SCID are alive and treated with IVIG until to find a matched donor for receiving HSCT.