Gene mutations responsible for primary immunodeficiency disorders: A report from the first primary immunodeficiency biobank in Iran

In the last decade, much effort has been devoted to establish biobanks for different research purposes. It has been a long-standing need to create a biobank for PID patients in Iran. Construction of such a biobank as a resource center of data and genome contents facilitates identification of genetic defects underlying different types of PID, in spite of the generation of descriptive statistics. We created a PIDB in order to stop the ad-hoc research studies, which may not have standard quality of sampling, processing and storage.

In our population, 30 different PIDs were diagnosed and categorized into 8 main groups. This is a preliminary report of our PID biobank and database. Our study showed that antibody deficiency is the most common group of PIDs in Iran, which is consistent with other studies [29, 33–37]. The proportion of patients with antibody deficiency in total is almost similar to previous reports from Iran but lower than the last report from ESID (26 vs. 57%) [4, 37]. Congenital defect of phagocyte number and/or function is the second most predominant PID in our study, similar to studies from France, Malaysia, Korea, USIDNET⁸, Iran and Iceland [4, 36–39], and is in contrast with studies from other registries that reported combined immunodeficiency with associated/syndromic feature as the second common one [33, 35, 39, 40]. Phagocyte defect involved 23.9% of our patients and 42% of PIDs in Oman [41]. However, much lower frequency has been observed in ESID, UK, Turkey and Spain [35, 39, 42]. Combined immunodeficiency with associated/syndromic feature was the third prevalent PID, which accounts for 10% of patients in accordance with studies from France, Malaysia and UK. This group of PID was formerly known as well-defined syndromes, but it has been changed into combined immunodeficiency with associated/syndromic feature in the updated IUIS. Innate immunity defects and auto inflammatory diseases are followed by combined immunodeficiency and disease of immune dysregulation. Complement deficiency was the least prevalent subcategory in our study and also in the other surveys [39, 43]. CVID¹ was the most frequent disorder in most studies [34, 39], which is in contrast with the last update of IPIDR that indicated SCID⁹ as the most common disorder in Iran [4].

It was not an unexpected finding that PID in males is more frequent than females (1.7:1), but we found a significant difference in sex distribution in CID⁷, combined immunodeficiency with associated/syndromic feature, antibody deficiency and auto inflammatory disorders compared to other PID groups. The fact that males are more affected by PID is partially related to known X-linked disorders. Our registry included only 10 BTK¹⁰ deficiencies, 1 CD-40 ligand deficiency, 2 WAS¹¹ and 1 IPEX¹² patients. An important finding is that, besides these known X-linked diseases, there is still a significant difference in gender distribution in the mentioned groups. This finding may suggest the presence of undiscovered X-linked patterns of inheritance in PID groups among our population. Few studies evaluated consanguinity in PID families. Our study is the first study to analyze consanguinity among different groups of PIDs, but no significant difference was observed. Recent studies and other registries from Islamic countries and also from Germany showed a higher rate of consanguineous marriage in parents of PID patients compared to the rate reported from the UK and Turkey [35, 42]. In our PID population, consanguinity was mostly observed in patients with CID⁵ and CID with associated/syndromic feature. Our study evaluated the history of any known/suspicious case of PID in family members of the patients, which was more frequent than in another report from Iran (48.9 vs. 28.9%) [4]. It is probably due to the consideration of positive family history of PID in relatives of patients who did not yet have a definite genetic diagnosis.

Diagnostic delay in our study (5 years and 6 months) was much higher than that of other studies. This may be due to ignorance of symptoms and mismanagements of patients by inept physicians. The clinical evidence for this fact is that 22 patients suffer from bronchiectasis (11.7%). The delay from onset of symptoms to diagnosis was shorter in CID⁷ with syndromic/associated feature, because these patients have significant presentations, distinctive features in childhood or intrauterine defects including coarse faces, microcephaly, mental retardation, dwarfism, and IUGR, among others which cannot be neglected. Our registry also reports 7 deaths due to primary immunodeficiency disease that can be partly related to delayed or undiagnosed type of disease. As patients with PID are struggling with various recurrent infections, lifelong, and no definite treatment is known except bone marrow transplantation, in some cases, they just receive therapies in order to control signs and symptoms. Consequently, these patients visit their clinical immunologists for follow up and renew their drugs frequently. Our last update revealed that 61 patients were not followed in the previous year, and we are unaware of their disease status. Mortality rate in our study (5.5%) is much lower when compared to the other report from Iran (18.7%) [4]. We established that most of the deceased patients suffered from SCID⁹; however, our study included few cases of SCID⁹ and other severe PID cases leading to death. We also observed that most of the affected patients are from low socioeconomic status. This might be due to a lower level of education and not being aware of the risks associated with consanguineous marriage. Other studies indicated that lack of accurate clinical PID diagnostic criteria, unawareness of general practitioners and lack of referring to physicians in cases with mild presentations cause PIDs not to be discovered properly. Societies with advanced social awareness report statistics closer to the actual quantities. Therefore, long-term projects for improving social knowledge about primary immunodeficiency diseases, their clinical presentations, consanguineous marriage and its genetic effect on occurrence of PIDs are planned. We began our cooperation with the Standing Committee of Public Health in the International Federation of Medical Students Association. This standing committee is responsible for raising awareness regarding global public health issues. As a rule, the earlier the diagnosis is made, the sooner the treatment can commence and the lower morbidity and mortality can be expected.