Lessons from Genetic Studies of Primary Immunodeficiencies in a Highly Consanguineous Population

Abstract

During the last decades, the study of primary immunodeficiencies (PIDs) has contributed tremendously to unravel novel pathways involved in a variety of immune responses. Many of these PIDs have an autosomal recessive (AR) mode of inheritance. Thus, the investigation of the molecular basis of PIDs is particularly relevant in consanguineous populations from Middle East and North Africa (MENA). Although significant efforts have been made in recent years to develop genetic testing across the MENA region, few comprehensive studies reporting molecular basis of PIDs in these settings are available. Herein, we review genetic characteristics of PIDs identified in 168 patients from an inbred Tunisian population. A spectrum of 25 genes involved was analyzed. We show that AR forms compared to X-linked or autosomal dominant forms are clearly the most frequent. Furthermore, the study of informative consanguineous families did allow the identification of a novel hyper-IgE syndrome linked to phosphoglucomutase 3 mutations. We did also report a novel form of autoimmune lymphoproliferative syndrome caused by homozygous FAS mutations with normal or residual protein expression as well as a novel AR transcription factor 3 deficiency. Finally, we identified several founder effects for specific AR mutations. This did facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families. All together, these findings highlight the specific nature of highly consanguineous populations and confirm the importance of unraveling the molecular basis of genetic diseases in this context. Besides providing a better fundamental knowledge of novel pathways, their study is improving diagnosis strategies and appropriate care.

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

“…These mechanisms fit well with outbred human populations . In contrast, in our consanguineous settings, we have now identified 4 different FAS homozygous mutations including those with preserved or absent Fas protein expression, while we identified only 3 heterozygous ALPS patients so far …”

“…It is well known that distribution of PIDs with more than 1 mode of transmission is often different in consanguineous populations as compared to outbred ones. Indeed, in our settings, the AR mode of inheritance accounted for most kindreds with chronic granulomatous disease, hyper‐IgM syndrome, and hyper‐IgE syndrome unlike what is reported in European, American, and Asian series and/or registries …”

“…45 In contrast, in our consanguineous settings, we have now identified 4 different FAS homozygous mutations including those with preserved or absent Fas protein expression, 17,46 while we identified only 3 heterozygous ALPS patients so far. 2 This novel AR mode of inheritance of ALPS-FAS with normal or decreased protein expression is definitely favored by the consanguineous environment. Similarly, we reported a novel AR mode of inheritance for the previously reported AD agammaglobulinemia caused by heterozygous dominant-negative de novo mutation in transcription factor 3 (TCF3) gene.…”

“…Moreover, there is cumulative evidence that the deeply rooted tradition of parental consanguinity in patients originating from Middle East and North Africa region has resulted in an increased burden of autosomal recessive (AR) PIDs since consanguinity favors the expression of recessive alleles . Indeed, the AR mode of inheritance is shown to be the most common in these highly endogamous populations and accounts for a majority of PIDs entities diagnosed in these settings …”

“…1 Indeed, the AR mode of inheritance is shown to be the most common in these highly endogamous populations and accounts for a majority of PIDs entities diagnosed in these settings. 2 Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of immune regulation resulting from defects of programmed cell death pathway, more commonly called apoptosis. This process is essential for immune homeostasis 3 and also helps maintain immunologic Abbreviations: AD, autosomal dominant; ALPS, autoimmune lymphoproliferative syndrome; AR, autosomal recessive; BPS, branch point sequence; DD, death domain; DNT, double-negative CD3+TCR / +CD4-CD8-T cells; FasL, Fas ligand; PIDs, primary immune deficiencies; PTB, polypyrimidine tract-binding protein; SF1, splicing factor 1 tolerance.…”