Ataxia-telangiectasia (A-T) is an autosomal recessive multisystem disorder characterized by progressive cerebellar degeneration, variable immunodeficiency, oculocutaneous telangiectasia, cancer susceptibility, and sensitivity to radiation (1, 2).

A-T patients represent a wide range of clinical manifestations, including progressive cerebellar ataxia, radiosensitivity, susceptibility to malignancies, and metabolic disorders. Other abnormalities, such as growth failure, poor pubertal development, insulin-resistant diabetes, gonadal atrophy, lung disease, cutaneous abnormality, and cardiovascular disease, have also been reported in A-T patients (3, 4). A-T patients have poor prognosis, and their survival time is approximately 25 years. The two most common causes of death in these patients are chronic pulmonary diseases and malignancy (5).

This syndrome is caused by biallelic pathogenic mutations in the ataxia-telangiectasia (ATM) gene containing 66 exons; of which, 62 are coding exons, spread over 150 kb of genomic DNA, with an open-reading frame of 9,168 nucleotides (6). This gene encodes a large protein (∼350 KDa) belonging to the phosphatidylinositol 3-kinase–related protein kinase (PIKK) family including ATR, DNAPKcs, mTOR, and SMG1 genes (6, 7). As a member of the PIKK family, ATM contains a kinase domain positioned between conserved C-terminal domains known as FAT (FRAP, ATR, and TRRAP proteins), PIKK kinase, and FATC domains (7). These domains control ATM’s kinase activity by interacting with regulatory proteins and inducing posttranslational modifications (7).

ATM function is important to B-and T-cell receptor development and class switch recombination (CSR) in activated B cells (8). In addition, ATM plays a critical role in the repair of DNA double-strand breaks, the regulation of the cell cycle, the stability of the genome, and the survival of cells (9).

The majority of ATM pathogenic variants are single-nucleotide variant (SNV) alterations, such as frameshift or nonsense variants, which are predicted to truncate the ATM protein (8). Patients carrying these types of ATM mutations develop the classic form of A-T (10, 11).

Other SNV pathogenic variants of ATM include missense and splicing variants. According to the Human Gene Mutation Database, the copy number variation (CNV) or large genomics alterations are detected in approximately 1%–10% of A-T patients (12, 13). However, limited information is available on the co-occurrence of SNV and CNV and its identified role or phenotype burden in A-T patients (8).

This study reports for the first time a case of a Tunisian child diagnosed with A-T syndrome, who carried compound heterozygous ATM pathogenic variants, detected by targeted NGS. The co-segregation of both mutations was analyzed in the parents.

The proband in this study is a 16-year-old girl who had been followed up since the age of 6 years when she first presented with ocular telangectasia, foot drop, and proximo-distal deficit of both inferior extremities as addressed first to the Pediatric Neurology Department and then to Genetic Department of Hedi Chaker Hospital-Sfax Tunisia. The family pedigree information was gathered, and blood samples were collected from the patient and her parents. The proband had been the subject of various diagnostic tests, including magnetic resonance imaging (MRI) of the brain and cervical region, ultrasound examinations of the heart and abdomen, electroencephalogram (EEG), and blood biochemical analysis involving α-fetoprotein (AFP), immunoglobulin (Ig), and ceruloplasmin level detection.

Written informed consent was obtained from all participants.

Ataxia-telangiectasia (A-T) is a rare disorder affecting multiple body systems. Typically, the degeneration of the nervous system begins between 6 and 18 months of age, resulting in being confined to a wheelchair by the age of 10 years. Cerebellar degeneration causes symptoms such as unsteady trunk movements, difficulty walking, lack of coordination, weak muscles, and sudden falls (16). The involuntary movements in A-T patients worsen over time, starting mildly in childhood and becoming more noticeable in adulthood. Movement disorders characterized by reduced movement are less common compared to those with excessive movement. Some patients might develop symptoms resembling Parkinson’s disease, such as stiffness and tremors when at rest (17).

It is well known that the mode of inheritance for A-T is autosomal recessive and caused by biallelic mutations in the ATM gene. The ATM protein plays a pivotal role in regulating several tumor suppressor proteins, mainly TP53, BRCA1, Chek2, RAD17, RAD9, and NBS1 (18, 19). These proteins, along with ATR kinase, are considered master controllers of cell cycle checkpoint signaling pathways, essential for the cell’s response to DNA damage and maintenance of genome stability (19, 20). Thus, when both copies of the ATM gene are inactivated (biallelic inactivation), it leads to A-T.

It is important to mention that in Tunisia, only two studies have investigated the clinical, immunological, and molecular (chromosomal instability) features without identifying the causal ATM gene mutation (21, 22). Therefore, our study is the first one that reports a Tunisian A-T patient harboring compound heterozygous mutations in the ATM gene, namely, a frameshift c.[3894dupT];p.(Ala1299CysfsTer3;rs587781823) and a splice site acceptor variant (c.[5763-2A>C],rs876659489). According to the literature, the frameshift variant had been previously identified in a homozygous state in Italian and Polish A-T patients (23, 24).

Globally, most ATM gene mutations involve frameshift or nonsense mutations located in the proximal, central, and distal regions of the ATM gene (25). Barone et al. demonstrated that the majority of ATM missense mutations in A-T are functionally linked to defects in expression and/or inactivation of kinase activity (26). Additionally, Jacquemin et al. showcased that, aside from resulting in the under-expression of the ATM protein, ATM missense mutations caused abnormal cytoplasmic localization of the protein (27).

A recent study on Iranian A-T patients reported that ATM nonsense and frameshift mutations are most frequent, leading to a more severe phenotype than missense or splice-site mutations (28). However, in Chinese A-T patients, the mutational spectrum of ATM is likely to be diverse and different, when largely compared to other ethnic areas (29). Biallelic ATM mutations combining the splice site variant with frameshift, nonsense, or missense mutations were less frequent than other compound mutations. Despite this, there is a recent case report that described a Chinese A-T patient diagnosed at 7 years of age with the compound heterozygous ATM genotype (frameshift combined with splice site ATM variant), who is similar to the proband in our case (30). This Chinese girl presented with growth retardation, ataxia, medium ocular telangiectasia, cerebellar atrophy, elevated serum alpha-fetoprotein (AFP) level, and normal serum levels of immunoglobulins, which are all similar to our proband.

Altogether, our patient had an onset of A-T syndrome at the age of 6 years with slow progression and a lack of basal ganglia manifestations, ruling out immunodeficiency, which may indicate that her mutations led to less severe neurodegenerative effects compared to other mutations in the ATM gene.

Furthermore, there is increasing evidence showing that heterozygous mutations in the ATM gene are associated with an increased risk of developing a wide spectrum of malignancies, including breast, stomach, and lung cancers (31). We observed that the Tunisian family consists of several members with various types of cancer such as lung, larynx, brain, and breast. In line with this report, we confirmed that the proband’s mother, who had breast cancer, carried the pathogenic ATM variant c.[3894dupT];p.(Ala1299CysfsTer3;rs587781823), which is most likely responsible for the malignancy.

Although there is currently no cure for A-T patients, there has been a rapid development of mutation-targeted therapeutic approaches. These advancements bring hope for potential treatment in specific A-T patients with ATM mutations (32). These mutations can be corrected, for example, using antisense morpholino oligonucleotide (AMO), read through compound (RTC), or micro-RNA (33, 34). In fact, AMOs have shown effectiveness in correcting type II and IV splicing mutations (35). Research has also revealed that functional ATM protein can be induced using RTCs to target premature termination codons in cells with ATM heterozygous nonsense mutations (33). Furthermore, gene editing approaches, such as CRISPR/Cas9, have been employed for targeting the ATM gene, offering a promising tool for new therapeutic approaches in treating this disease (36).

These in vitro tests shed light on the potential therapeutic applications of customized mutation-targeted therapies for A-T patients in the future. However, it is very important to note that this personalized approach profoundly relies on an exhaustive analysis of ATM gene mutations.

In summary, we report a case of an A-T patient carrying a compound heterozygous mutation c.[3894dupT];p.(Ala1299CysfsTer3;rs587781823) and c.[5763-2A>C rs876659489] splice acceptor variant in the ATM gene. Our findings extend the genotype spectrum of A-T in the Tunisian population and will allow timely decisions to be made in A-T diagnosis for better therapeutic management.

The datasets presented in this article are not readily available because of ethical and privacy restrictions. Requests to access the datasets should be directed to the corresponding author.

The studies involving humans were approved by the Comité de Protection des personnes CHU Hedi Chaker/CHU Habib Bourguiba sfax—Tunisia. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants' legal guardians/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

NA-B: Investigation, Methodology, Writing – original draft, Writing – review & editing. RA-D: Data curation, Investigation, Methodology, Writing – review & editing. DB: Formal analysis, Methodology, Writing – review & editing. SG: Conceptualization, Formal analysis, Writing – review & editing. OJ: Formal analysis, Writing – review & editing. HK: Writing – review & editing. CC: Supervision, Validation, Writing – review & editing. RM-G: Conceptualization, Formal analysis, Supervision, Writing – original draft, Writing – review & editing.