New research by the genetics team, led by Dr. Andre Megarbane, assistant dean for research and department chair, alongside associate professors Dr. Cybel Mehawej and Dr. Eliane Chouery at LAU’s Gilbert and Rose-Marie Chagoury School of Medicine, was featured in the November issue of the Journal of Clinical Immunology, making it the second notable publication for the team in a month.

Co-funded by the President’s Intramural Research Fund (PIRF)  and the L’Oréal-UNESCO For Women in Sciences grant, the study explores how a genetic variant in the SH3GL1 gene, leading to a deficiency in its encoded protein, the endophilin A2, impairs antibody production in humans.

In this interview, the team expands on the study and the possibilities provided by Next Generation Sequencing.

Can you elaborate on the case that led to your study and the findings?

The case that led to our study was that of a 14-year-old patient from a Lebanese family presenting since the age of 18 months with a rare and unexplained immune deficiency. The patient exhibited symptoms that suggested an abnormal immune response, but standard genetic testing had not yielded conclusive results as the genetic cause of his condition had not yet been identified. We performed whole-exome sequencing, which allowed us to identify a novel genetic cause of primary immunodeficiency (PID). Our findings enabled us to link, for the first time, biallelic mutations in the SH3GL1 gene to a disease in humans, which is a primary antibody deficiency. Biallelic mutations refer to mutations affecting both the paternal and maternal forms (alleles) of a single gene.

What implications does your discovery have on treating this condition?

The discovery of the cause of a genetic disease is the first step toward implementing efficient therapeutic approaches. Indeed, by discovering that a mutation in the SH3GL1 gene encoding the protein endophilin A2 is linked to immune deficiency, particularly an antibody deficiency, we established a link between this protein and the humoral immune response—a type of immune response whereby B cells recognize an antigen or pathogen in the blood.

Our studies have demonstrated that reduced expression of this protein disrupts the normal development and activation of B lymphocytes, which are essential cells involved in the humoral immune response that produces antibodies. Further investigations will enable us to better understand the pathological mechanism, which may help scientists implement new therapies.

This information allows clinicians to diagnose this condition more accurately and potentially intervene earlier, preventing severe outcomes. Furthermore, identifying the genetic cause of the disease within the family will enable parents and relatives to receive proper genetic counseling, empowering them to make informed decisions about their health.

Why was the link between this homozygous frameshift variant in the SH3GL1 gene and immune deficiency not detected previously?

Despite the tremendous development witnessed in the immunogenetics field, many primary immunodeficiencies remain unrecognized and their genetic cause so far undiscovered. Indeed, of the 10,000 genes estimated to be expressed in the immune system, only around 500 have been linked to PIDs. This is mainly due to the rarity of these conditions and the challenging interpretation of genetic data, especially in the immunogenetic field. For example, in the case of PIDs, the same genetic disease can exhibit variable expressivity, even within a single family. Additionally, environmental factors, such as infections, may influence the clinical outcome, further complicating the interpretation of genetic findings.

In particular, with regard to the SH3GL1, previous studies mainly focused on the involvement of endophilin A2 in central nervous system processes and cancer, and its involvement in immune deficiencies may have been overlooked in earlier studies. Only recently have studies in mouse models highlighted the critical role of endophilin A2 in modulating immune responses, revealing that the SH3GL1 gene, which encodes this protein, is not yet widely recognized as a key player in the immune system.

Are most of your studies prompted by a patient case?

Yes, most of our studies are indeed driven by patient cases. When clinicians come across rare or unexplained conditions or observe familial patterns of certain diseases, they refer their patients to our department to investigate the underlying genetic causes and establish an accurate diagnosis. These cases often serve as the foundation for our research, leading to important discoveries that not only benefit the individual patient but also contribute to a broader understanding of genetic diseases. By carefully examining these cases, we are able to identify novel genetic variants and mechanisms that may help scientists understand the normal functioning of our organism. This knowledge then paves the way for developing innovative therapeutic approaches. Therefore, patients are at the heart of our research, guiding us from start to finish.

This discovery comes soon after your groundbreaking study on the POLD3 gene and hearing impairment. How do you explain the speed or frequency with which these new findings are reached?

The speed and frequency of these new findings can be attributed to several factors. First, the availability of extensive genetic data has significantly increased in recent years through Next Generation Sequencing approaches, providing us with a considerably precious resource for analysis. Our team has also developed the expertise to analyze such complex data through years of experience, and following several trainings at various centers abroad.

That said, in our country as in several other countries in the Middle East and North Africa (MENA) region, many sociocultural, geographical and religious factors have favored the practice of consanguineous marriages (or marriages between relatives), which itself favors the occurrence of rare genetic disorders. Therefore, investigating patients from populations with a high prevalence of consanguinity provides the possibility to identify new diseases not encountered globally yet.

Last but not least, as Louis Pasteur famously said, “Chance favors the prepared mind,” and the combination of our team’s preparation, the support we receive, and the growing wealth of data has allowed us to achieve these rapid advances.

This interview has been edited and condensed for the sake of clarity.

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