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Article

Spectrum of Genetic Diseases in Tunisia: Current Situation and Main Milestones Achieved

by
Nessrine Mezzi
1,2,
Olfa Messaoud
1,
Rahma Mkaouar
1,
Nadia Zitouna
1,
Safa Romdhane
1,
Ghaith Abdessalem
1,
Cherine Charfeddine
1,3,
Faouzi Maazoul
4,
Ines Ouerteni
4,
Yosr Hamdi
1,5,
Anissa Zaouak
6,
Ridha Mrad
4,
Sonia Abdelhak
1 and
Lilia Romdhane
1,2,*
1
Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis 1002, Tunisia
2
Department of Biology, Faculty of Sciences of Bizerte, Université Tunis Carthage, Jarzouna 7021, Tunisia
3
High Institute of Biotechnology of Sidi Thabet, Biotechpole of Sidi Thabet, University of Manouba, Ariana 2080, Tunisia
4
Department of Congenital and Hereditary Diseases, Charles Nicolle Hospital, Tunis 1002, Tunisia
5
Laboratory of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia
6
Department of Dermatology, Research Unit Genodermatosis and Cancer LR12SP03, Habib Thameur Hospital, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1002, Tunisia
*
Author to whom correspondence should be addressed.
Genes 2021, 12(11), 1820; https://doi.org/10.3390/genes12111820
Submission received: 27 September 2021 / Revised: 30 October 2021 / Accepted: 3 November 2021 / Published: 19 November 2021
(This article belongs to the Special Issue Genetic Tests)
Browse Figures
Versions Notes

Abstract

:
Genetic diseases in Tunisia are a real public health problem given their chronicity and the lack of knowledge concerning their prevalence and etiology, and the high rates of consanguinity. Hence, we performed systematic reviews of the literature in order to provide a more recent spectrum of these disorders and to expose the challenges that still exist to tackle these kinds of diseases. A manual textual data mining was conducted using MeSH and PubMed databases. Collected data were classified according to the CIM-10 classification and the transmission mode. The spectrum of these diseases is estimated to be 589 entities. This suggests remarkable progress through the development of biomedical health research activities and building capacities. Sixty percent of the reported disorders are autosomal recessive, which could be explained by the high prevalence of endogamous mating. Congenital malformations (29.54%) are the major disease group, followed by metabolic diseases (22%). Sixty percent of the genetic diseases have a known molecular etiology. We also reported additional cases of comorbidity that seem to be a common phenomenon in our population. We also noticed that epidemiological data are scarce. Newborn and carrier screening was only limited to pilot projects for a few genetic diseases. Collected data are being integrated into a database under construction that will be a valuable decision-making tool. This study provides the current situation of genetic diseases in Tunisia and highlights their particularities. Early detection of the disease is important to initiate critical intervention and to reduce morbidity and mortality.

1. Introduction

Rare diseases (RDs) are defined differently from one jurisdiction or organization to another [1]. In the USA, a rare disease (RD) is a disease affecting fewer than 200,000 people in the population (https://rarediseases.info.nih.gov, accessed on 24 September 2021). In Europe, a prevalence of less than 1/2000 people was specified to define a RD [2]. In Japan, any disorder affecting 1 in 2500 people is a RD [3]. In an attempt to define a consensus about an international definition of RD, Ritcher and his colleagues proposed a global average of 40 cases/100,000 people with an average of 1/2500 people [3]. In the Arab world, including Tunisia, there is no standard definition of RD. RDs imply a great global burden and a significant challenge for health systems resulting from unmatched patients’ needs and the absence of equal access to diagnosis and treatment [4]. Nearly 6000 RDs have been identified around the world (https://www.rarediseaseday.org/, accessed on 24 September 2021). Only 5% of them have an FDA-approved treatment (https://globalgenes.org/rare-diseases-facts-statistics/, accessed on 24 September 2021).
Approximately 72% of RDs are attributed to genetic factors (https://www.rarediseaseday.org/, accessed on 24 September 2021). Genetic diseases are generally early-onset and life-threatening conditions [5]. About 30% of affected individuals die before five years [5]. Genetic diseases particularly concern the Arab world, where at least 1890 disorders have been identified (https://www.cags.org.ae/en, accessed on 24 September 2021). Congenital and genetic diseases are a major cause of infant mortality and handicap among Arab countries [6]. The spread of genetic diseases in the Arab world, especially rare conditions, was largely explained by socio-cultural factors [7,8]. Indeed, the highest rates of consanguinity with an extreme prevalence of first-cousin unions were described among Arab families, also known by their large size [9]. In addition, high paternal and maternal age have also been documented among Arabs [6].
Tunisia, a middle-income country, is situated in a strategic position at the crossroad of Europe, the Middle East and Sub-Saharan Africa. The current population is estimated to be 11,860,516 in November 2020, with a population growth rate assessed to 1.11% (https://tradingeconomics.com/tunisia; https://www.worldometers.info/world-population, accessed on 24 September 2021). About 98% of Tunisians are Muslims living with other minorities, such as Christians and Jews [10]. The country has been inhabited since the Paleolithic period [11]. Berbers, also called Amazigh, are the indigenous people of Tunisia [12,13]. This has been well confirmed by the investigation of the HLA class I and class II gene profiles among Tunisians, which shows the Berber origin of the present-day Tunisian population [14]. Throughout its history, the Tunisian population has witnessed successive invasions and several migratory flows during prehistoric and historic periods [13], thus shaping its genetic landscape [10].
Tunisia is characterized by the improvement of health system indicators [15]. In the MENA region, Tunisia has the highest life expectancy with remarkable improvements in maternal and infant mortality [16]. This could be explained by the implementation of social programs aiming to reduce the burden of communicable diseases (CD) [15]. Consequently, epidemiological data show that non-communicable diseases (NCD), such as genetic disorders, exceed CD [17]. To a certain extent, this can be explained by changes in national economic activities, family structure, and lifestyle that could foster the rising burden of NCD [18]. Similarly to other Arab countries, familial and geographic endogamy is a deeply conserved rule in Tunisia with remarkable historical and social roots with rates ranging up to 38.0% despite the remarkable socio-demographic changes [7,19,20,21]. This socio-cultural feature has been found to be strongly associated with the expression of rare genetic diseases [19,22]. In a previous study, we reported on the preliminary spectrum of genetic diseases in Tunisia. Such conditions are considered as real problems of public health in Tunisia as their spectrum encompasses 346 genetic disorders [23]. A large proportion is represented by autosomal recessive diseases (62.9%), followed by autosomal dominant diseases highlighting the impact of inbreeding in their emergence [23]. In the present work, we performed a systematic review of the literature relative to genetic diseases in Tunisia in order to (i) “provide a more recent spectrum” of these disorders in the Tunisian population, (ii) identify the type of potential health interventions that could be proposed for these conditions in Tunisia, and (iii) to shed light on challenges that still exist.

2. Materials and Methods

2.1. Systematic Review of Literature Related to Genetic Diseases Spectrum in Tunisia

A comprehensive review of published data was conducted mainly using the MeSH and PubMed databases. The list of genetic diseases was obtained after querying the MeSH database using the keywords “genetic diseases”. The query results were further combined to additional keywords “tunis*” using the PubMed search tool. We focused only on papers published from 2010 to August 2021. The final query on PubMed was the following: ((“Genetic Diseases, Inborn”[Mesh]) AND (Tunis*)) AND ((“2010”[Date—Publication]: “2021”[Date—Publication])).
The retained papers (n = 970) were included in the meta-analysis and were curated manually. They were completely screened for disease name, OMIM ID, inheritance mode, associated gene(s), germinal mutation(s) (according to HGVS nomenclature), and epidemiological parameters (prevalence, incidence, and patient counts). We also searched for the same information from the grey literature (including technical or research reports, doctoral thesis, conference proceedings, etc.). From the selected documents reporting on genetic diseases in the Tunisian population, a recursive search for additional documents was performed using the authors’ names of referring physicians and researchers in Tunisia.
We used the tenth version of the World Health Organization (WHO) International Classification of Disease (WHO ICD-10) in order to provide a clustering of the genetic diseases in different pathological groups. Our previous data on the genetic diseases’ spectrum published in 2011 have been compared to the updated data using the Fisher test, considering 5% as a statistical significance threshold. The data have been stored in a local database for subsequent analyses (Figure 1).

2.2. Systematic Review of Literature Focusing on Newborn and/or Carrier Screening for Genetic Diseases among Tunisians

To get knowledge about the current genetic disease screening situation in Tunisia, a selective literature search was carried out. Multiple keywords have been used to develop an advanced PubMed query string as below:
(“Genetic Diseases, Inborn”[Mesh]) AND ((“Mass Screening”[Mesh] OR “Diagnosis”[Mesh] OR “Maternal Serum Screening Tests”[Mesh] OR “High-Throughput Screening Assays”[Mesh] OR “Neonatal Screening”[Mesh] OR “Multiphasic Screening”[Mesh] OR “Genetic Carrier Screening”[Mesh] OR “Diagnostic Screening Programs”[Mesh] OR “Direct-To-Consumer Screening and Testing”[Mesh] OR “Prenatal Diagnosis”[Mesh] OR “Noninvasive Prenatal Testing”[Mesh] OR “Preimplantation Diagnosis”[Mesh] OR “Mandatory Testing”[Mesh]) AND (Tunis*))
Only studies dealing with genetic disease screening among Tunisians were kept. In addition, we asked referring experts (clinicians, researchers) with whom we collaborate in order to provide more information concerning screening for these disorders. Moreover, grey literature was an important resource in this part of the systematic review.
Furthermore, we have defined a list of genetic diseases frequently described among Tunisians based on epidemiological data, essentially patients’ counts. The experience feedback of our collaborators was of great value in this step of analysis. We have checked the eligibility of the identified commonly-reported genetic diseases for systematic newborn and/or carrier screening in our country by responding to key questions relative to newborn screening and using the seven ACOG carrier-screening criteria mentioned in their committee opinion in 2017. These criteria are the following (a) well-defined phenotype, (b) detrimental effect on the quality of life, (c) cognitive or physical impairment, (d) surgical or medical intervention is required, (e) an early life onset, (f) availability of prenatal diagnosis, and (g) carrier frequency of 1 in 100 or greater. Evaluation of these criteria was conducted by a genetic counselor.

3. Results

In this study, we present the actual situation of genetic diseases in Tunisia. Compared to what has been published in 2011, 243 additional genetic conditions have been identified, with an average of approximately 23 genetic diseases reported every year. Thus, the total number of genetic diseases in Tunisia amounts to 589 clinical and/or genetic entities, in which 41.3% come from the present data mining.

3.1. Classification of Genetic Diseases According to WHO-ICD 10

We opted for the international medical classification (WHO ICD-10) of genetic diseases described in the Tunisian population. Therefore, such classification revealed that congenital malformations, deformations, and chromosomal abnormalities are the most commonly reported (29.54%). Endocrine, nutritional, and metabolic diseases are the next most frequent group of diseases (22%), followed by diseases of the nervous system (15.45%) (Figure 2). We report a slight increase in the following disease groups: diseases of the ear and mastoid process and diseases of the eye and adnexa. We also noticed that diseases of the circulatory system are highly reported. A comparison between genetic diseases spectrum data of 2011 and the updated data of our study highlighted a significant difference in the distribution of disease classes (Fisher test p-value = 9.9 × 10−4).

3.2. Classification According to the Inheritance Mode

Among genetic diseases derived from this analysis (243 genetic diseases), autosomal recessive diseases (AR) are the most frequent (54.7%), followed by autosomal dominant (AD) disorders (27.16%). X-linked (XL) conditions were encountered 5% of the time. Diseases transmitted with both AR and AD (AR, AD) are more prevalent than in data reported before 2011. Remarkably, diseases inherited via mitochondrial mode are becoming more reported (8.2%). In order to check for an eventual change in the inheritance mode distribution between the two datasets, we have compared our current data to that of the previous spectrum. We found a significant difference (Fisher’s test; p-value = 5 × 10−4). Despite this difference, the whole spectrum of genetic diseases described among Tunisians (589 genetic diseases) has kept the same pattern illustrated by the high frequency of AR diseases (60%) followed by the AD conditions (24.3%) (Figure 2).

3.3. Molecular Etiology of the Genetic Diseases in the Tunisian Population

Sixty-one percent (61 %) of the 589 genetic diseases have a known molecular etiology (358 genetic diseases), meaning that the responsible gene with at least one mutation has been identified among Tunisian patients. About 69% of these diseases are autosomal recessive, 16.2% are autosomal dominant, 7% are caused by a mutation in mitochondrial genes, 6% are X-linked, and only 0.3% are Y-linked or sporadic. Autosomal dominant or autosomal recessive diseases are encountered at 1.2% (Figure 3).
Among these diseases, 21 conditions were of unknown molecular etiology before the last decade (reported in the study of Romdhane and Abdelhak, 2011) (Table 1). Eleven diseases mainly belong to the endocrine, nutritional, and metabolic disorders class. Three are diseases of the nervous system, and one is a bleeding disorder. The eight remaining correspond to congenital malformations, deformations, and chromosomal abnormalities (Table 1). Next-generation sequencing has been used to elucidate the molecular etiology in four of them (Table 1). Referring to the original study conducted by Romdhane and Abdelhak in 2011, the Tunisian mutational spectrum included 420 mutations (98% nuclear, 2% mitochondrial) (Romdhane et al. 2011) (23). Here, the global spectrum comprises more than 896 mutations. These mutations affect 313 genes: 95.5% nuclear (299 genes) and 4.5 % mitochondrial (14 genes). The actual Tunisian mutational spectrum encompasses 429 (48%) founder mutations responsible for 197 genetic diseases. Allelic heterogeneity was noticed for 154 genes (Table S1 Supplementary Data). HBB, G6PD, and CFTR genes were the most mutated genes among Tunisians with at least 25 alterations.

3.4. Comorbidity among Tunisians

Comorbidity is defined as the expression of another disease in addition to the primary disease. This phenomenon has been reported among Tunisian families (Romdhane et al., 2016) [42]. In our updated data, we have identified fourteen co-occurrences of multiple diseases since 2016 (Table 2). All of them belong to the genetic disease–genetic disease class of comorbid associations (in other words, both diseases are caused by a mutation in a single gene or multiple genes) with a consanguinity history among six of them. Both familial (6) and individual (8) comorbidities have been identified. They are either with the same mode of transmission or not. The comorbid associations include diseases of the same pathological group, for example, genodermatoses (Ichthyosis congenital and Erythrokeratodermia variabilis, Xeroderma pigmentosum group C, and Rothmund Thomson syndrome) or not (Table 2).

3.5. Phenotypic Features of Genetic Diseases in Tunisia

Atypical phenotypes are also reported and characterize several genetic diseases among Tunisians. By atypical clinical presentations, we mean unusual symptoms of the disease. Chanarin–Dorfman syndrome, palmoplantar keratoderma, juvenile Parkinson’s disease, and multiple endocrine neoplasia type 2A were described in Tunisian patients with unusual presentations (Table 3).

3.6. Epidemiology of Genetic Diseases in Tunisia

For epidemiological parameters, we focused on the frequency of the whole reported disease spectrum by targeting either the prevalence or the incidence. We noticed the paucity of such epidemiological data as only 26 (4.6%) genetic diseases described among Tunisians have defined prevalence and/or incidence (Table 4). For some genetic disorders (five diseases), the epidemiological data are described among specific ethnic groups or in specific regions. For the remaining diseases, only the number of studied patients and/or families is reported. In an attempt to compare these epidemiological data, we tried to use the same scale of a rare disease threshold prevalence in Europe (1/2000). By aligning to this definition, we found that seven diseases largely exceed this threshold. For ten others, the available epidemiological data suggests that they are ultra-rare diseases (Table 4).

3.7. Current Situation of Newborn and/or Carrier Screening for Genetic Diseases in Tunisia

On 1 July 2021, the second PubMed-MeSH query described above yielded 732 results, of which 26 articles have been retained for further analysis. Three articles (in French) found in Google Scholar have also been included. Ultimately 29 articles were screened. In all of these studies, the authors highlight the key role of screening for genetic diseases as a state-run health program in Tunisia. However, neonatal newborn and carrier screenings were limited to pilot experiments for only six conditions, and they have not been replicated or extended geographically to the level of the country. Systematic newborn screening for hearing impairment is exclusively conducted in the governorate of Sfax in the south (Table 5). In fact, 16 disorders are likely frequent among Tunisians, of which 10 are part of the Recommended Uniform Screening Panel. All of them are associated with founder and/or recurrent mutations, and 14 met all the 7 ACOG criteria, with 2 late-onset diseases (Table S2 Supplementary data).

4. Discussion

In this study, we attempted to provide a comprehensive and up-to-date overview of the genetic disease spectrum described among Tunisians. Our findings showed that the number of reported genetic conditions increased from 346 to 589 in the last eleven years (2010–2021). This highlights remarkable progress in the availability of molecular diagnosis of genetic diseases in Tunisia. The development of biomedical health research activities, the building capacities in this field, and the use of high-throughput sequencing technologies facilitated by international collaborations, have played a critical role in this progress [7].
Genetic disorders present a health burden, especially among inbred populations, including Arab countries and several African communities [9,75,76]. Here, in the recent spectrum, most of the genetic diseases described among Tunisians are autosomal recessive (59.8%). A slight reduction is noticed compared to data reported in 2011; however, their frequency is still high, which could be explained by the socio-cultural features in the Tunisian population [19]. Indeed, consanguineous marriages, with an extreme predominance of first-cousin marriages associated with large family sizes, are responsible for the high prevalence of recessively inherited conditions among Tunisians [20,22,23,77]. It has been proven that there is an increased risk of almost eight times for expressing a recessive disease among first-cousin marriage’s progeny [22].
Another impact of the elevated rate of consanguinity and inbreeding is the co-occurrence of two or more phenotypes within the same family [42]. Comorbidity, described particularly in inbred populations, makes genetic counseling and prenatal diagnosis challenging [42,44]. The study of Romdhane and her colleagues revealed 75 genetic disease co-occurrences identified in Tunisian patients. Thirty-nine (39) of them have been reported among Tunisian consanguineous families [42]. Since then, 14 additional comorbidities of genetic diseases in Tunisians were reported in our study, for which NGS techniques had largely contributed to the molecular diagnosis. Consanguinity was noted in six of them.
Several variants, either in the same gene or in related genes, were correlated with the high frequency of genetic diseases in inbred communities [76]. In the current report, we have found that the Tunisian mutational spectrum includes more than 896 mutations affecting 313 genes. Among these mutated genes, allelic heterogeneity was identified for 154 of them. Such characteristics render the diagnosis difficult and could lead to misdiagnosis, especially in developing countries, such as Tunisia [7,10]. Screening for founder mutations among endogamous populations is a cost-effective molecular diagnosis strategy [10], but it may be inefficient when applied to atypical rare phenotypes and comorbidities (Mezzi et al., Unpublished). Consequently, whole-exome sequencing (WES), could be an alternative choice to elucidate the molecular etiology of such conditions and is always recommended, especially when targeted mutation screening and/or targeted gene sequencing results are negative or ambiguous [78,79]. In Tunisia, molecular investigation of genetic diseases is mainly conducted using Sanger DNA sequencing. However, since 2013, we note that next-generation sequencing (NGS) has become more affordable to the scientific community, mainly through international collaborations. We found that the use of high-throughput sequencing has led to the identification of the molecular bases of at least 45 mendelian diseases described in Tunisians.
Autosomal dominant diseases were found in 24.5% of reported Tunisian patients. Although intrafamilial marriages have no important effect on the prevalence of autosomal dominant diseases, significant consequences on the expression of such disorders could not be completely excluded [7]. Indeed, consanguineous unions could increase the likelihood of homozygosity for dominant genetic variations [20,80], which could induce more severe phenotypes and even atypical ones [20,80]. This was the case for a large consanguineous Tunisian family with granular corneal dystrophy type I in which homozygous members for a TGFBI mutation were the severely most affected [81]. Allelic comorbidity involving a dominant disease illustrated by the consanguineous family reported by Sfar et al., is also an excellent example of such an effect [82]. The parents, who presented a mild phenotype of neonatal hyperparathyroidism, were heterozygous for a CASR gene mutation. Their daughter had a severe hyperparathyroidism phenotype because of her homozygous state for the same mutation [82].
Accurate prevalence and incidence rates are crucial to developing an understanding of a disease’s natural history and population burden [83]. However, among the 589 genetic disorders described among Tunisians, only 26 (4.6%) have a defined prevalence and/or incidence yet without systematic updates. Some genetic diseases, including familial hypercholesterolemia (12.12/2000) and hemoglobinopathies (89.6/2000), are particularly frequent in Tunisia compared to Europe, where they are reported as rare diseases. Several others are rare and even ultra-rare, depending on the defined threshold. The scarcity of accurate epidemiological data could lead to misdiagnosis [84] and indicates the necessity of comprehensive epidemiology and patient registry creation [7,20,85]. Thus far, only three patient registries have been set for genetic disorders in Tunisia, namely, Gaucher Disease (http://www.maladie-gaucher-tunisie.org/, accessed on 24 September 2021), Fanconi Anemia (http://fanconi-tunisie.net/, accessed on 24 September 2021), and bleeding disorders [86]. Furthermore, they are not systematically updated, and they are facing personal patient data security problems and storage systems issues. Building rare genetic diseases registries in developing countries is challenging [84,86]. The main obstacle is the drastic lack of well-defined policies and the paucity of common protocols for these registries [84]. Moreover, data on rare genetic diseases are usually unharmonized (archived in hand-written form or in simple excel files). Consequently, data treatment and handling are time-consuming tasks [85]. In addition, the funding needed for the infrastructure of these registries could be challenging, as not all countries can cover their costs [85]. Considering the fact that epidemiological studies of rare and extremely rare diseases are difficult to set at the level of the country (as for classical epidemiological studies), we highly recommend national registries to establish either specific to each disease or to a group of diseases in order to have not only a better estimation of their figures but also for better care interventions. Moreover, developing a population-specific genetic diseases database is undoubtedly needed to have a complete overview of their spectrum in a given population. This informative online database will be a hopeful starting point for healthcare experts and researchers [87].
Molecular data availability on relatively frequent genetic rare diseases in inbred populations could be an ideal way to boost current research focusing on targeted therapies, including gene and mutation-specific therapies, hence leading to the implementation of precision medicine. Several diseases identified in the Tunisian population are subject to targeted therapy based on their genetic information. Bloom syndrome (BS) is a DNA-repair disease characterized by a high risk of cancer at an early age [88]. It has been established that a correct diagnosis should be clearly set before using chemotherapy in BS patients because drug dose is highly dependent on the disease severity degree [88] while conventional chemo or radiotherapy would lead to a profound genomic instability and, consequently, enhanced carcinogenesis. In the same way, knowing the gene or the mutation is also fundamental for implementing efficient therapy. Indeed, improved cochlear implant outcomes have been observed among deaf Tunisian individuals for whom the hearing loss is related to GJB2 mutations and who were implanted at an early age [89,90]. Drugs targeting mutations are an innovative therapeutic approach in cystic fibrosis (CF) [91,92]. CF is a common genetic life-shortening condition in the Caucasian population, and it is not so rare in North Africa [93]. The CFTR gene has accumulated multiple founder mutations that could be used as a target for personalized therapy [94]. Lumacaftor was tested as an effective mutation-specific therapy for African-American CF patients targeting the shared founder mutation that is also reported in the Tunisian population [95]. Gene therapy is a promising strategy for the permanent treatment of genetic diseases. LGMD2C has the highest incidence in North Africa, and it is caused by the predominant founder deletion c.521delT in the SGCE gene [96,97]. A gene therapy trial has been performed targeting patients with these founder mutations as a crucial inclusion criterion [98]. Nine Tunisian patients were involved in this trial [98]. With mutation-specific therapies being under development, a correct diagnosis is more than ever mandatory for assessing whether patients are eligible or not for adequate treatments.
The increased focus on genetic diseases in Tunisia over the last decades has been spurred mainly by the clinical and molecular investigations intended to improve the diagnosis. Nevertheless, genetic services are lacking and are not equally distributed across the country. Indeed, only three main medical genetic services are available: Charles Nicolle hospital in Tunis, Farhat Hached hospital in Sousse, and Habib bourguiba hospital in Sfax. A unit for congenital and inherited diseases was recently built at the “Mongi Slim hospital” in La Marsa, providing cytogenetic tests. Furthermore, breast and cervical cancer screening has been integrated into basic health care services within the framework of national cancer control plans (Ministère de la Santé, Direction de Santé, Plan pour la lutte contre le cancer 2015–2019) (Tunis: Ministère de la Santé, 2015). In addition, the establishment of an NGS platform in Institut Pasteur de Tunis, allowed the setting up of molecular diagnosis of familial cancers, thus contributing to the better characterization and widening of the mutation spectrum of BRCA1/2 genes in the Tunisian population [99]. The increased prevalence of cystic fibrosis (CF) among Tunisian children and the potentially severe complications associated with this disease justify the management of CF by a multidisciplinary team of clinicians in the child pulmonology referral unit in Bechir Hamza children’s Hospital of Tunis [54]. In this unit, englobing the largest national series, patients are managed by several therapeutic strategies (respiratory physiotherapy, antibiotherapy, aerosol therapy, vitamin therapy, inhaled corticosteroids, etc.) [54,94]. Genetic counseling and prenatal diagnosis are also proposed to families [54]. This example illustrates the importance of the referral centers for better knowledge of the disease where adequate clinical and molecular competencies are available, but it is still insufficient as the commitment of the national authorities is required in order to support these centers by providing adequate technological platforms.
From a public health perspective, experts and policymakers have opted that newborn and carrier screening should be conducted as a state-run program [100,101]. This will allow early detection of genetic conditions and congenital disorders, leading to reduced health disparities and mortality at a young age [102,103]. The infant mortality rate is an indicator of a state’s health, and reducing this rate is an explicit goal of sustainable development (2030 United Nations Sustainable Development Goals). Several genetic conditions are recommended to be screened among newborns and/or at-risk individuals around the world. Among these, we have the Recommended Uniform Screening Panel (RUSP) issued by the U.S. Health and Human Services (HSS) Federal Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). The RUSP includes 35 core conditions (for which newborn screening is highly recommended) and 26 secondary conditions (for which newborn screening is optional). Furthermore, a data-driven evaluation has been conducted in which an Expanded Carrier Screening (ECS) panel of 172 conditions have been defined and met all the required criteria defined by the American College of Obstetricians and Gynecologists [104,105]. In the MENA region, reducing genetic condition expression, particularly those recessively inherited, is a salient issue mainly due to their high prevalence because of inbreeding and the severe expression in newborns [106,107]. However, among several countries of this region, newborn screening is not introduced systematically as a health policy, and it is only limited to pilot projects [106,108]. In fact, only Gulf states have a newborn screening panel for 20 metabolic conditions [106,109]. Egypt and Palestine also have a national neonatal screening plan for congenital hypothyroidism and phenylketonuria [110,111,112]. Of the disorders recommended to be screened (RUSP and ECS panel), 49% are described among Tunisian patients (Table S3 Supplementary Data), representing 19% of the genetic disease spectrum in Tunisia and could be considered, therefore, as a potential target for intervention. The absence of such an intervention in Tunisia could be explained by the inability of the Ministry of Health and of the social security system to ensure adequate care or health coverage for individuals screened as positive [108,113]. Consequently, we propose, instead of systematic neonatal screening, to conduct cascade carrier screening with specific regional programs that take into account the most frequent diseases and underlying deleterious founder alleles. This helps to decrease morbidity and mortality, as well as to improve the quality of life and life expectancy for patients with genetic diseases.
A comprehensive genetic education and premarital genetic counseling programs can also help to reduce the burden of genetic diseases in inbred communities [114,115]. In Bahrain, educational programs aimed at high school children have had a marked beneficial effect in lessening the incidence of sickle cell disease [116]. It has been suggested that raising public awareness of sickle cell disease through prevention campaigns using informational programs with different communication media would be efficient to reduce the burden of the disease in the population in addition to programs that have proven their efficiencies, such as student screening programs, premarital counseling, and newborn screening [117].
Patient support groups could act as key support for rare genetic diseases. As stated earlier, hearing loss constitutes a frequent disease group in our population. In an attempt to improve the auditory health in the Tunisian population, hearing screening and awareness-raising campaigns are being organized by NGOs, such as ICHARA, in the frame of a science shop project participatory research support [118].

5. Conclusions

Our study provides a better knowledge of the genetic diseases spectrum in Tunisia, which is useful for this country, as well as for neighboring countries, in order to improve the diagnosis, to reduce misdiagnosis, and therefore, patients will have earlier and better management. This would also help to avoid possible complications and reduce the costs of managing these diseases. Molecular and genetic data for these diseases are becoming more widely available through the development of biomedical health research activities and access to high-throughput next-generation sequencing. However, the Tunisian population still faces challenges, especially in the case of dual diagnosis and co-occurrence in the same patient or family, which delays the appropriate patient management. Taking this into account, in addition to the relatively high genetic and mutational heterogeneity, we recommend the creation of diagnostic referral centers that leverage some technologies, such as whole-exome sequencing, as a first intention tool for genetic disease elucidation in the country. These specialized structures could potentially offer accurate molecular diagnostic services at a lower cost and allow faster, efficient patient management. Furthermore, patient management should include multidisciplinary team investigators working in a well-defined care pathway. Vigilant monitoring of emerging clinical manifestations is recommended, especially in the case of genetic disorders. Furthermore, studies are needed to accurately set the epidemiological data of genetic diseases aiming to implement better and appropriate healthcare measures. Patient support groups have a significant role to play in promoting patient voice and influencing the decision-makers.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/genes12111820/s1, Table S1: Mutated genes among Tunisians, Table S2: Frequent genetic diseases in Tunisia, Table S3: Genetic diseases screened recommended for newborn and/or carrier screening.

Author Contributions

Conceptualization: N.M., L.R. and S.A. Methodology/literature search: N.M. and L.R. Data collection: N.M., O.M., R.M. (Rahma Mkaouar), N.Z., S.R., G.A., C.C., F.M., I.O., Y.H., A.Z., R.M. (Ridha Mrad), S.A. and L.R. Data analysis: N.M. Validation: L.R., O.M., S.A. and R.M. (Ridha Mrad), Writing—original draft preparation: N.M. Writing—review and editing: N.M., O.M., R.M. (Rahma Mkaouar), N.Z., G.A., C.C., F.M., I.O., A.Z., R.M. (Ridha Mrad), S.A. and L.R. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Tunisian Ministry of Public Health (Personal costs), the Ministry of Higher Education and Scientific Research (LR20IPT05), and the project of young researchers’ promotion for their contributions to this study (19PEJC06-07). N.M. is a recipient of a MOBIDOC fellowship, funded by The Ministry of Higher Education and Scientific Research through the PromEssE project and managed by the ANPR. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors are grateful to clinicians’ collaborators for sharing their field experience and feedback that was of great value in our study.

Conflicts of Interest

The authors declare that they have no conflict of interest regarding this study.

References

  1. Ferreira, C.R. The burden of rare diseases. Am. J. Med. Genet. Part A 2018, 179, 885–892. [Google Scholar] [CrossRef]
  2. Thomas, S.; Caplan, A. The Orphan Drug Act Revisited. JAMA 2019, 321, 833–834. [Google Scholar] [CrossRef]
  3. Richter, T.; Nestler-Parr, S.; Babela, R.; Khan, Z.M.; Tesoro, T.; Molsen, E.; Hughes, D.A. Rare Disease Terminology and Definitions-A Systematic Global Review: Report of the ISPOR Rare Disease Special Interest Group. Value Health 2015, 18, 906–914. [Google Scholar] [CrossRef] [Green Version]
  4. Sara Cannizzo, V.L.; Palla, I.; Pirri, S.; Trieste, L.; Triulzi, I.; Turchetti, G. Rare diseases under different levels of economic analysis: Current activities, challenges and perspectives. RMD Open 2018, 4 (Suppl. 1), e000794. [Google Scholar] [CrossRef]
  5. Luo, E.; Liu, H.; Zhao, Q.; Shi, B.; Chen, Q. Dental-craniofacial manifestation and treatment of rare diseases. Int. J. Oral. Sci. 2019, 11, 9. [Google Scholar] [CrossRef] [PubMed]
  6. Lihadh Al-Gazali, H.H.; Al-Arrayad, S. Genetic disorders in the Arab world. Br. Med. J. 2006, 333, 831–834. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Romdhane, L.; Mezzi, N.; Hamdi, Y.; El-Kamah, G.; Barakat, A.; Abdelhak, S. Consanguinity and inbreeding in health and disease in North African populations. Annu. Rev. Genom. Hum. Genet. 2019, 20, 155–179. [Google Scholar] [CrossRef] [PubMed]
  8. Zayed, H. The Arab genome: Health and wealth. Gene 2016, 592, 239–243. [Google Scholar] [CrossRef] [PubMed]
  9. Tadmouri, G.O.; Nair, P.; Obeid, T.; Al Ali, M.T.; Al Khaja, N.; Hamamy, H.A. Consanguinity and reproductive health among Arabs. J. Reprod. Health 2009, 6, 17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Romdhane, L.; Kefi, R.; Azaiez, H.; Ben Halim, N.; Dellagi, K.; Abdelhak, S. Founder mutations in Tunisia: Implications for diagnosis in North Africa and Middle East. Orphanet J. Rare Dis. 2012, 7, 52. [Google Scholar] [CrossRef] [Green Version]
  11. Frigi, S.; Cherni, L.; Fadhlaoui-Zid, K.; Benammar-Elgaaied, A. Ancient local evolution of African mtDNA haplogroups in Tunisian Berber populations. Hum. Biol. 2010, 82, 367–384. [Google Scholar] [CrossRef] [PubMed]
  12. Kefi, R.; Hsouna, S.; Ben Halim, N.; Lasram, K.; Romdhane, L.; Messai, H.; Abdelhak, S. Phylogeny and genetic structure of Tunisians and their position within Mediterranean populations. Mitochondrial DNA 2015, 26, 593–604. [Google Scholar] [CrossRef]
  13. Mughal, M. In Tunisia, in Native Peoples of the World: An Encyclopedia of Groups, Cultures, and Contemporary Issues; Routledge: New York, NY, USA, 2013; pp. 688–689. [Google Scholar]
  14. Hajjej, A.; Almawi, W.Y.; Hattab, L.; El-Gaaied, A.; Hmida, S. HLA Class I and Class II Alleles and Haplotypes Confirm the Berber Origin of the Present Day Tunisian Population. PLoS ONE 2015, 10, e0136909. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Ben Romdhane, H.; Tlili, F.; Skhiri, A.; Zaman, S.; Phillimore, P. Health system challenges of NCDs in Tunisia. Int. J. Public Health 2015, 60, 39–46. [Google Scholar] [CrossRef] [PubMed]
  16. Arfa, C.; Achouri, H. Tunisia: “Good Practice” in expanding health care coverage: Lessons from reforms in a country in transition. In Good Practices in Health Financing Lessons from Reforms in Low-and Middle-Income Countries; The World Bank: Washington, DC, USA, 2008; Volume 20, pp. 335–438. [Google Scholar]
  17. Ben Romdhane, H.; Husseini, A.; Jabbour, S. Non-Communicable Diseases—II: Focus on Cardiovascular Diseases; Cambridge University Press: New York, NY, USA, 2012; pp. 164–177. [Google Scholar]
  18. Atek, M.; Traissac, P.; El Ati, J.; Laid, Y.; Aounallah-Skhiri, H.; Eymard-Duvernay, S.; Mézimèche, N.; Bougatef, S.; Béji, C.; Boutekdjiret, L. Obesity and association with area of residence, gender and socio-economic factors in Algerian and Tunisian adults. PLoS ONE 2013, 8, e75640. [Google Scholar] [CrossRef] [Green Version]
  19. Ben Halim, N.; Bouafif, N.B.A.; Romdhane, L.; Atig, R.K.B.; Chouchane, I.; Bouyacoub, Y.; Arfa, I.; Cherif, W.; Nouira, S.; Talmoudi, F. Consanguinity, endogamy, and genetic disorders in Tunisia. J. Community Genet. 2013, 4, 273–284. [Google Scholar] [CrossRef] [Green Version]
  20. Romdhane, L.; Halim, N.B.; Rejeb, I.; Kefi, R.; Bouyacoub, Y.; Rekaya, M.B.; Messai, H.; Messaoud, O.; Riahi, Z.; Bonnet, C. Specific aspects of consanguinity: Some examples from the Tunisian population. J. Human Hered. 2014, 77, 167–174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Zakaria, D. Etude de L’endogamie D’origine Régionale, de la Distribution de la Consanguinité Apparente et du Comportement Intergénérationnel Dans le Choix Matrimonial en Tunisie. Intérêt des Noms de Famille et de L’isonymie Maritale. Ph.D. Thesis, Faculty of Science, University of Tunis, Tunis, Tunisia, 1999. [Google Scholar]
  22. Ben Halim, N.; Hsouna, S.; Lasram, K.; Rejeb, I.; Walha, A.; Talmoudi, F.; Messai, H.; Sabrine Ben Brick, A.; Ouragini, H.; Cherif, W.; et al. Differential impact of consanguineous marriages on autosomal recessive diseases in Tunisia. Am. J. Hum. Biol. 2016, 28, 171–180. [Google Scholar] [CrossRef]
  23. Romdhane, L.; Abdelhak, S.; Research Unit on Molecular Investigation of Genetic Orphan Diseases and Collaborators. Genetic diseases in the Tunisian population. Am. J. Med. Genet. A 2011, 155, 238–267. [Google Scholar] [CrossRef]
  24. Kharrat, M.; Trabelsi, S.; Chaabouni, M.; Maazoul, F.; Kraoua, L.; Ben Jemaa, L.; Gandoura, N.; Barsaoui, S.; Morel, Y.; M’Rad, R.; et al. Only two mutations detected in 15 Tunisian patients with 11beta-hydroxylase deficiency: The p.Q356X and the novel p.G379V. Clin. Genet. 2010, 78, 398–401. [Google Scholar] [CrossRef] [PubMed]
  25. Kallabi, F.; Hadj Salem, I.; Ben Salah, G.; Ben Turkia, H.; Ben Chehida, A.; Tebib, N.; Fakhfakh, F.; Kamoun, H. Molecular characterization of X-linked adrenoleukodystrophy in a Tunisian family: Identification of a novel missense mutation in the ABCD1 gene. Neurodegener. Dis. 2013, 12, 207–211. [Google Scholar] [CrossRef]
  26. Chakroun, A.; Ben Said, M.; Ennouri, A.; Achour, I.; Mnif, M.; Abid, M.; Fakhfakh, F.; Kamoun, H. Long-term clinical follow-up and molecular testing for diagnosis of the first Tunisian family with Alstrom syndrome. Eur. J. Med. Genet. 2016, 59, 444–451. [Google Scholar] [CrossRef] [Green Version]
  27. Salah, G.B.; Salem, I.H.; Masmoudi, A.; Rhouma, B.B.; Turki, H.; Fakhfakh, F.; Ayadi, H.; Kamoun, H. Chromosomal instability associated with a novel BLM frameshift mutation (c. 1980-1982delAA) in two unrelated Tunisian families with Bloom syndrome. J. Eur. Acad. Dermatol. Venereol. 2014, 28, 1318–1323. [Google Scholar] [CrossRef] [PubMed]
  28. Kek, H.E.H.; Wigren, E.; Jlizi, A.; Zahra, K.; Pellechia, D.; Vinciguerra, C.; Meddeb, B.; Elggaaied, A.B.A.; Gouider, E. First report of molecular diagnosis of Tunisian. hemophiliacs A: Identification of 8 novel. causative mutations. Diagn. Pathol. 2012, 7, 93. [Google Scholar]
  29. Cherif, W.; Turkia, B.; Rhouma, B.; Riahi, I.; Chemli, J.; Amaral, O.; Miranda, S.; Caillaud, C.; Kaabachi, N.; Tebib, N. Molecular diagnosis of Gaucher disease in Tunisia. Pathol. Biol. 2012, 61, 59–63. [Google Scholar] [CrossRef] [PubMed]
  30. Mazzucchelli, I.; Garofoli, F.; Decembrino, L.; Castiglia, D.; Tadini, G.; Bellingeri, A.; Borghesi, A.; Tzialla, C.; Manzoni, P.; Stronati, M. A novel LAMA3 mutation in a newborn with junctional epidermolysis bullosa herlitz type. Neonatology 2011, 99, 188–191. [Google Scholar] [CrossRef] [PubMed]
  31. Khiari, H.M.; Lesca, G.; Malafosse, A.; Mrabet, A. A novel exon 3 mutation in a Tunisian patient with Lafora’s disease. J. Neurol. Sci. 2011, 304, 136–137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Tinsa, F.; Ben Romdhane, M.; Boudabous, H.; Bel Hadj, I.; Brini, I.; Tebib, N.; Louati, H.; Bekri, S.; Boussetta, K. A Novel Mutation c.153 C > A in a Tunisian Girl with Wolman Disease and Unusual Presentation: Hemophagocytic Lymphohistiocytosis. J. Pediatr. Hematol. Oncol. 2018, 41, e193–e196. [Google Scholar] [CrossRef] [PubMed]
  33. Jaafar, N.; Moleirinho, A.; Kerkeni, E.; Monastiri, K.; Seboui, H.; Amorim, A.; Prata, M.J.; Quental, S. Molecular characterization of maple syrup urine disease patients from Tunisia. Gene 2013, 517, 116–119. [Google Scholar] [CrossRef]
  34. Valente, E.M.; Logan, C.V.; Mougou-Zerelli, S.; Lee, J.H.; Silhavy, J.L.; Brancati, F.; Iannicelli, M.; Travaglini, L.; Romani, S.; Illi, B.; et al. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat. Genet. 2010, 42, 619–625. [Google Scholar] [CrossRef]
  35. Mkaouar-Rebai, E.; Chamkha, I.; Mezghani, N.; Ben Ayed, I.; Fakhfakh, F. Screening of mitochondrial mutations in Tunisian patients with mitochondrial disorders: An overview study. Mitochondrial DNA 2013, 24, 163–178. [Google Scholar] [CrossRef]
  36. Said, M.B.; Chouchène, E.; Salem, S.B.; Daoud, K.; Largueche, L.; Bouassida, W.; Benzina, Z.; Ayadi, H.; Söderkvist, P.; Matri, L.; et al. Posterior microphthalmia and nanophthalmia in Tunisia caused by a founder c.1059_1066insC mutation of the PRSS56 gene. Gene 2013, 528, 288–294. [Google Scholar] [CrossRef]
  37. Rekik, S.; Sakka, S.; Romdhane, S.B.; Amer, Y.B.; Lehkim, L.; Farhat, N.; Mahfoudh, K.B.; Authier, F.J.; Dammak, M.; Mhiri, C. Novel splicing dysferlin mutation causing myopathy with intra-familial heterogeneity. Mol. Biol. Rep. 2020, 47, 5755–5761. [Google Scholar] [CrossRef]
  38. Chkioua, L.; Grissa, O.; Leban, N.; Gribaa, M.; Boudabous, H.; Turkia, H.B.; Ferchichi, S.; Tebib, N.; Laradi, S. The mutational spectrum of hunter syndrome reveals correlation between biochemical and clinical profiles in Tunisian patients. BMC Med. Genet. 2020, 21, 111. [Google Scholar] [CrossRef]
  39. Ouesleti, S.; Brunel, V.; Ben Turkia, H.; Dranguet, H.; Miled, A.; Miladi, N.; Ben Dridi, M.F.; Lavoinne, A.; Saugier-Veber, P.; Bekri, S. Molecular characterization of MPS IIIA, MPS IIIB and MPS IIIC in Tunisian patients. Clin. Chim. Acta 2011, 412, 2326–2331. [Google Scholar] [CrossRef] [PubMed]
  40. Chkioua, L.; Khedhiri, S.; Grissa, O.; Aloui, C.; Turkia, H.B.; Ferchichi, S.; Miled, A.; Froissart, R.; Acquaviva, C.; Laradi, S. Genetic basis of cystinosis in Tunisian patients: Identification of novel mutation in CTNS gene. Meta Gene 2015, 5, 144–149. [Google Scholar] [CrossRef] [PubMed]
  41. Pohler, E.; Mamai, O.; Hirst, J.; Zamiri, M.; Horn, H.; Nomura, T.; Irvine, A.D.; Moran, B.; Wilson, N.J.; Smith, F.J.; et al. Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nat. Genet. 2012, 44, 1272–1276. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Romdhane, L.; Messaoud, O.; Bouyacoub, Y.; Kerkeni, E.; Naouali, C.; Cherif Ben Abdallah, L.; Tiar, A.; Charfeddine, C.; Monastiri, K.; Chabchoub, I.; et al. Comorbidity in the Tunisian population. Clin. Genet. 2016, 89, 312–319. [Google Scholar] [CrossRef]
  43. Mrabet, H.; Borhani-Haghighi, A.; Koseoglu, E.; Mutlu, M.; Baydemir, R.; Nafissi, S.; Eschebbi, S.; Delibas, E.; Samangooie, S.; Yetkin, F.; et al. Association of amyotrophic lateral sclerosis and Behcet’s disease: Is there a relationship? A multi-national case series. Clin. Rheumatol. 2012, 31, 733–738. [Google Scholar] [CrossRef]
  44. Sayeb, M.R.Z.; Laroussi, N.; Bonnet, C.; Romdhane, L.; Mkaouar, R.; Zaouak, A.; Marrakchi, J.; Abdessalem, G.; Messaoud, O.; Bouchniba, O.; et al. A Tunisian family with a novel mutation in the gene CYP4F22 for lamellar ichthyosis and co-occurrence of hearing loss in a child due to mutation in the SLC26A4 gene. Int. Soc. Dermatol. 2019, 58, 1439–1443. [Google Scholar] [CrossRef]
  45. Ghedira, N.; Lagarde, A.; Ben Ameur, K.; Elouej, S.; Sakka, R.; Kerkeni, E.; Chioukh, F.Z.; Olschwang, S.; Desvignes, J.P.; Abdelhak, S.; et al. Clinical profile of comorbidity of rare diseases in a Tunisian patient: A case report associating incontinentia pigmenti and Noonan syndrome. BMC Pediatr. 2018, 18, 286. [Google Scholar] [CrossRef] [Green Version]
  46. Tabebi, M.; Charfi, N.; Kallabi, F.; Alila-Fersi, O.; Ben Mahmoud, A.; Tlili, A.; Keskes-Ammar, L.; Kamoun, H.; Abid, M.; Mnif, M.; et al. Whole mitochondrial genome screening of a family with maternally inherited diabetes and deafness (MIDD) associated with retinopathy: A putative haplotype associated to MIDD and a novel MT-CO2 m.8241T>G mutation. J. Diabetes Complicat. 2017, 31, 253–259. [Google Scholar] [CrossRef] [PubMed]
  47. Baya, W.; Fredj, F.B.; Hassine, I.B.; Anoun, J.; Mzabi, A.; Karmani, M.; Rezgui, A.; Laatiri, M.A.; Kechrid, C.L. Systemic lupus erythematosus, antiphospholipid syndrome and Hashimoto thyroiditis occurring in a patient with Niemann-Pick disease: A second case. Pan Afr. Med. J. 2020, 36, 367. [Google Scholar] [CrossRef] [PubMed]
  48. Louhichi, N.; Bahloul, E.; Marrakchi, S.; Othman, H.B.; Triki, C.; Aloulou, K.; Trabelsi, L.; Mahfouth, N.; Ayadi-Mnif, Z.; Keskes, L.; et al. Thyroid involvement in Chanarin-Dorfman syndrome in adults in the largest series of patients carrying the same founder mutation in ABHD5 gene. Orphanet J. Rare Dis. 2019, 14, 112. [Google Scholar] [CrossRef]
  49. Charfeddine, C.; Dallali, H.; Abdessalem, G.; Ghedira, K.; Hamdi, Y.; Elouej, S.; Landoulsi, Z.; Delague, V.; Lagarde, A.; Levy, N.; et al. Identification of a CDH12 potential candidate genetic variant. for an autosomal dominant form of transgrediens and progrediens palmoplantar keratoderma in a Tunisian family. J. Hum. Genet. 2020, 65, 397–410. [Google Scholar] [CrossRef] [PubMed]
  50. Ben Romdhan, S.; Sakka, S.; Farhat, N.; Triki, S.; Dammak, M.; Mhiri, C. A Novel SYNJ1 Mutation in a Tunisian Family with Juvenile Parkinson’s Disease Associated with Epilepsy. J. Mol. Neurosci. 2018, 66, 273–278. [Google Scholar] [CrossRef]
  51. Blibech, R.; Gharbi, Y.; Mrad, A.; Zahra, H.; Mahjoub, T.; Belhaj, A.; Laatiri, Z.; Kastally, R.; Rosa, R. Incidence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Tunisian populations. Nouv. Rev. Fr. d’Hématol. 1989, 31, 189–191. [Google Scholar]
  52. Fattoum, S. Evolution of hemoglobinopathy prevention in Africa: Results, problems and prospect. Mediterr. J. Hematol. Infect. Dis. 2009, 1, e2009005. [Google Scholar] [CrossRef]
  53. Zilber Nelly, K.E.; Miriam, A. The Libyan Creutzfeldt-Jakob disease focus in Israel: An epidemiologic evaluation. Neurology 1991, 41, 1385. [Google Scholar] [CrossRef]
  54. Boussetta, K.; Khalsi, F.; Bahri, Y.; Belhadj, I.; Tinsa, F.; Messaoud, T.B.; Hamouda, S. Cystic fibrosis in Tunisian children: A review of 32 children. Afr. Health Sci. 2018, 18, 664–670. [Google Scholar] [CrossRef] [Green Version]
  55. Kharfi, M.; Khaled, A.; Mokhtar, I.; Kamoun, M. Atopic dermatitis in Tunisia: Epidemiological and clinical aspects. Ann. Dermatol. Venereol. 2001, 128, 623–625. [Google Scholar]
  56. Brick, A.S.B.; Laroussi, N.; Mesrati, H.; Kefi, R.; Bchetnia, M.; Lasram, K.; Halim, N.B.; Romdhane, L.; Ouragini, H.; Marrakchi, S. Mutational founder effect in recessive dystrophic epidermolysis bullosa families from Southern Tunisia. Arch. Dermatol. Res. 2014, 306, 405–411. [Google Scholar] [CrossRef]
  57. Ayed, S.; Ghorbel, M.; Nacef, L.; Daghfous, F.; Osman, N.B.; Reguig, R.; Lachhab, M.J.L.T.m. The exfoliation syndrome in Tunisia. Tunis. Med. 1990, 68, 19–22. [Google Scholar]
  58. Ben Abdallah, M.; Zehani, S. Registre des Cancers Nord.-Tunisie 1995–1998; Institut Salah Azaiez: Tunis, Tunisia, 2004. [Google Scholar]
  59. Frikha, M.; Mseddi, S.; Elloumi, M.; Bouaziz, M.; Khanfir, A.; Mnif, J.; Saad, A.; Souissi, T. Fanconi disease: Study of 43 cases in Southern Tunisia. Arch. Pediatr. Organe Off. Soc. Fr. Pediatr. 1998, 5, 1200–1205. [Google Scholar] [CrossRef]
  60. Slimane, M.; Pousse, H.; Maatoug, F.; Hammami, M.; Farhat, M.B. Phenotypic expression of familial hypercholesterolaemia in central and southern Tunisia. Atherosclerosis 1993, 104, 153–158. [Google Scholar] [CrossRef]
  61. Turkia, B.; Tebib, N.; Azzouz, H.; Abdelmoula, M.S.; Chehida, B.; Chemli, J.; Monastiri, K.; Chaabouni, M.; Sanhagi, H.; Zouari, B. Incidence of mucopolysaccharidoses in Tunisia. Tunis. Med. 2009, 87, 782–785. [Google Scholar]
  62. Nasrallah, F.; Hadj-Taieb, S.; Chehida, A.B.; Jelassi, A.; Massoued, S.B.; Charfi, M.; Zidi, W.; Amri, F.; Helel, K.B.; Mejaoual, H. Nonketotic hyperglycinemia in tunisia. Report upon a series of 69 patients. Neuropediatrics 2020, 51, 349–353. [Google Scholar] [CrossRef] [PubMed]
  63. Chehida, A.B.; Messaoud, S.B.; Abdelaziz, R.B.; Mansouri, H.; Boudabous, H.; Hakim, K.; Ali, N.B.; Ameur, Z.B.; Sassi, Y.; Kaabachi, N. A lower energetic, protein and uncooked cornstarch intake is associated with a more severe outcome in glycogen storage disease type III: An observational study of 50 patients. J. Pediatr. Endocrinol. Metab. 2018, 31, 979–986. [Google Scholar] [CrossRef] [PubMed]
  64. Laradi, S.; Monastiri, K.; Ferchichi, S.; Nabli, N.; Rea, P.A.; Limam, H.B.; Mansour, R.B.; Bousoffara, R.; Yacoub, M.; Froissart, R. Les mucopolysaccharidoses (MPS) sont des maladies de surcharge lysosomiale. Ann. Biol. Clin. 2001, 59, 100–104. [Google Scholar]
  65. McNally, E.M.; Passos-Bueno, M.R.; Bönnemann, C.G.; Vainzof, M.; de Sa Moreira, E.; Lidov, H.; Othmane, K.B.; Denton, P.H.; Vance, J.M.; Zatz, M. Mild and severe muscular dystrophy caused by a single gamma-sarcoglycan mutation. Am. J. Hum. Genet. 1996, 59, 1040. [Google Scholar] [PubMed]
  66. Moussa, S.A.-B.; Moussa, A.; Lovecchio, T.; Kourda, N.; Najjar, T.; Jilani, S.B.; El Gaaied, A.; Porchet, N.; Manai, M.; Buisine, M.-P. Identification and characterization of a novel MLH1 genomic rearrangement as the cause of HNPCC in a Tunisian family: Evidence for a homologous Alu-mediated recombination. Fam. Cancer 2009, 8, 119–126. [Google Scholar] [CrossRef]
  67. Ben-Bassat, I.; Feinstein, A.; Ramot, B. Selective vitamin B12 malabsorption with proteinuria in Israel. Clinical and genetic aspects. Isr. J. Med. Sci. 1969, 5, 62–68. [Google Scholar]
  68. Dridi, M.-F.B.; Turkia, H.B.; Azzouz, H.; Chehida, A.B.; Abdelaziz, R.B.; Tebib, N. Les maladies héréditaires du métabolisme en Tunisie: Défis, acquis, espoirs. Arch. Pediatr. Organe Off. Soc. Fr. Pediatr. 2015, 5, 3–4. [Google Scholar] [CrossRef]
  69. Ben Rekaya, M.; Jerbi, M.; Messaoud, O.; Ben Brick, A.S.; Zghal, M.; Mbarek, C.; Chadli-Debbiche, A.; Jones, M.; Mokni, M.; Boussen, H.; et al. Further evidence of mutational heterogeneity of the XPC gene in Tunisian families: A spectrum of private and ethnic specific mutations. BioMed Res. Int. 2013, 2013, 316286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  70. Ouali, F.; Siala, H.; Bibi, A.; Hadj Fredj, S.; Dakhlaoui, B.; Othmani, R.; Ouenniche, F.; Zouari, F.; Bouguerra, B.; Rezigua, H.; et al. Prenatal diagnosis of hemoglobinopathies in Tunisia: An 18 years of experience. Int. J. Lab. Hematol. 2016, 38, 223–232. [Google Scholar] [CrossRef] [PubMed]
  71. Oueslati, S.; Hadj Fredj, S.; Belhaj, R.; Siala, H.; Bibi, A.; Messaoud, T. Preliminary study of haplotypes linked to the rare cystic fibrosis E1104X mutation. Acta Physiol. Hung. 2015, 102, 86–93. [Google Scholar] [CrossRef] [Green Version]
  72. Abed, A.B.; Saad, H.; Mustpha, R.; Chiha, M.; Gamra, B. Early hearning screening by otoacoustic emissions and auditory brain stem response in Nabeul. Tunis. Med. 2013, 91, 643–647. [Google Scholar]
  73. Guellouz, N.; Mansour, B.; Ouederni, M.; Jabnoun, S.; Kacem, S.; Ch, M.; Kastally, R.; Chahed, M.; Khrouf, N. Neonatal screening of G6PD deficiency in Tunisia. Arch. L’Inst. Pasteur Tunis 2010, 87, 69–76. [Google Scholar]
  74. Hajer, S.; Neila, T.; Sondess, H.F.; Fekria, O.; Nabila, A.; Mahbouba, K.; Melika, D.; Faida, O.; Amina, B.; Raja, B. A lower-cost protocol for sickle cell disease neonatal screening in Tunisia. Ann. Saudi Med. 2012, 32, 49–52. [Google Scholar] [CrossRef] [PubMed]
  75. Verma, I.C.; Puri, R.D. Global burden of genetic disease and the role of genetic screening. Semin. Fetal. Neonatal. Med. 2015, 20, 354–363. [Google Scholar] [CrossRef]
  76. Zlotogora, J. Autosomal recessive diseases among the Israeli Arabs. Hum. Genet. 2019, 138, 1117–1122. [Google Scholar] [CrossRef] [PubMed]
  77. Messaoud, O.; Rekaya, M.B.; Ouragini, H.; Benfadhel, S.; Azaiez, H.; Kefi, R.; Gouider-Khouja, N.; Mokhtar, I.; Amouri, A.; Boubaker, M.S.; et al. Severe phenotypes in two Tunisian families with novel XPA mutations: Evidence for a correlation between mutation location and disease severity. Arch. Dermatol. Res. 2012, 304, 171–176. [Google Scholar] [CrossRef]
  78. Zhang, F.; Guo, X.; Zhang, Y.; Wen, Y.; Wang, W.; Wang, S.; Yang, T.; Shen, H.; Chen, X.; Tian, Q. Genome-wide copy number variation study and gene expression analysis identify ABI3BP as a susceptibility gene for Kashin–Beck disease. J. Hum. Genet. 2014, 133, 793–799. [Google Scholar] [CrossRef]
  79. Monies, D.; Abouelhoda, M.; AlSayed, M.; Alhassnan, Z.; Alotaibi, M.; Kayyali, H.; Al-Owain, M.; Shah, A.; Rahbeeni, Z.; Al-Muhaizea, M.A.J.H.g. The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. Hum. Genet. 2017, 136, 921–939. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Richmond, C.M.; Campbell, S.; Foo, H.W.; Lunke, S.; Stark, Z.; Moody, A.; Bannister, E.; Greenway, A.; Brown, N. Rapid Identification of Biallelic SPTB Mutation in a Neonate with Severe Congenital Hemolytic Anemia and Liver Failure. Mol. Syndr. 2020, 11, 50–55. [Google Scholar] [CrossRef]
  81. Bouyacoub, Y.; Falfoul, Y.; Ouederni, M.; Sayeb, M.; Chedli, A.; Chargui, M.; Sassi, H.; Chakroun Chenguel, I.; Munier, F.L.; El Matri, L.; et al. Granular type I corneal dystrophy in a large consanguineous Tunisian family with homozygous p.R124S mutation in the TGFBI gene. Ophthalmic Genet. 2019, 40, 329–337. [Google Scholar] [CrossRef]
  82. Sfar, S.; Bzéouich, A.A.; Kerkeni, E.; Bouaziz, S.; Najjar, M.F.; Chouchane, L.; Monastiri, K. A novel CASR mutation in a Tunisian FHH/NSHPT family associated with a mental retardation. Mol. Biol. Rep. 2012, 39, 2395–2400. [Google Scholar] [CrossRef]
  83. John, J.N.; Sid, E.; Zhu, Q. Recurrent Neural Networks to Automatically Identify Rare Disease Epidemiologic Studies from PubMed. In Proceedings of the AMIA Annual Symposium Proceedings, San Diego, CA, USA, 30 October–3 November 2021; p. 325. [Google Scholar]
  84. De Antonio, M.; Dogan, C.; Daidj, F.; Eymard, B.; Puymirat, J.; Mathieu, J.; Gagnon, C.; Katsahian, S.; Filnemus Myotonic Dystrophy Study Group; Hamroun, D.; et al. The DM-scope registry: A rare disease innovative framework bridging the gap between research and medical care. Orphanet J. Rare Dis. 2019, 14, 122. [Google Scholar] [CrossRef] [PubMed]
  85. Zayed, H.; Ouhtit, A.; El Bekay, R. An Arab registry for type 1 diabetes: Global benefits for type 1 diabetes patients. Curr. Med. Res. Opin. 2016, 32, 1681–1684. [Google Scholar] [CrossRef]
  86. Elmahmoudi, H.; Chalbi, A.; Ben-Lakhal, F.; Borji, W.; Zahra, K.; Zorgan, M.; Meddeb, B.; Gouider, E. Regional registry of bleeding disorders in Tunisia. J. Haemoph. 2012, 1, 3. [Google Scholar] [CrossRef]
  87. Iourov, I.Y.; Vorsanova, S.G.; Yurov, Y.B.; Bertrand, T. VIII World Rett Syndrome Congress & Symposium of rare diseases, Kazan, Russia. Mol. Cytogenet. 2018, 11, 61. [Google Scholar]
  88. Ayed, F.F.-B.; Douira-Khomsi, W.; Rhayem, S.; Jelassi, M.; Zribi, H.; Chaabouni, M.; Khemiri, M.; Bellagha, I.; Barsaoui, S. Burkitt lymphoma in a child with Bloom syndrome. Arch. Pédiatr. 2016, 23, 382–384. [Google Scholar] [CrossRef]
  89. Riahi, Z.; Chahed, H.; Jaafoura, H.; Zainine, R.; Messaoud, O.; Naili, M.; Nagara, M.; Hammami, H.; Laroussi, N.; Bouyacoub, Y. A novel frameshift mutation (c. 405delC) in the GJB2 gene associated with autosomal recessive hearing loss in two Tunisian families. Int. J. Pediatr. Otorhinolaryngol. 2013, 77, 1485–1488. [Google Scholar] [CrossRef] [PubMed]
  90. Riahi, Z.; Hammami, H.; Ouragini, H.; Messai, H.; Zainine, R.; Bouyacoub, Y.; Romdhane, L.; Essaid, D.; Kefi, R.; Rhimi, M. Update of the spectrum of GJB2 gene mutations in Tunisian families with autosomal recessive nonsyndromic hearing loss. Gene 2013, 525, 1–4. [Google Scholar] [CrossRef] [PubMed]
  91. Amaral, M. Novel personalized therapies for cystic fibrosis: Treating the basic defect in all patients. J. Intern. Med. 2015, 277, 155–166. [Google Scholar] [CrossRef] [PubMed]
  92. Connett, G. Lumacaftor-ivacaftor in the treatment of cystic fibrosis: Design, development and place in therapy. Drug Des. Dev. Ther. 2019, 13, 2405–2412. [Google Scholar] [CrossRef] [Green Version]
  93. Arora, K.; Yarlagadda, S.; Zhang, W.; Moon, C.; Bouquet, E.; Srinivasan, S.; Li, C.; Stokes, D.C.; Naren, A. Personalized medicine in cystic fibrosis: Genistein supplementation as a treatment option for patients with a rare S1045Y-CFTR mutation. Am. J. Physiol.–Lung Cell. Mol. Physiol. 2016, 311, L364–L374. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Messaoud, T.; Bibi, A.; Elion, J.; Férec, C.; Fattoum, S. Molecular epidemiology of cystic fibrosis in Tunisia. Ann. Biol. Clin. 2005, 63, 627–630. [Google Scholar]
  95. Zhang, X.; Hothi, J.S.; Zhang, Y.H.; Srinivasan, S.; Stokes, D.C.; Zhang, W. c. 3623G> A mutation encodes a CFTR protein with impaired channel function. Respir. Res. 2016, 17, 1–6. [Google Scholar] [CrossRef] [Green Version]
  96. El Kerch, F.; Ratbi, I.; Sbiti, A.; Laarabi, F.Z.; Barkat, A.; Sefiani, A. Carrier frequency of the c.525delT mutation in the SGCG gene and estimated prevalence of limb girdle muscular dystrophy type 2C among the Moroccan population. Genet. Test. Mol. Biomark. 2014, 18, 253–256. [Google Scholar] [CrossRef] [Green Version]
  97. Siala, O.; Kammoun Feki, F.; Louhichi, N.; Hadj Salem, I.; Gribaa, M.; Elghzel, H.; Saad, A.; Triki, C.; Fakhfakh, F. Molecular prenatal diagnosis of muscular dystrophies in Tunisia and postnatal follow-up role. Genet. Test. 2008, 12, 581–586. [Google Scholar] [CrossRef]
  98. Herson, S.; Hentati, F.; Rigolet, A.; Behin, A.; Romero, N.B.; Leturcq, F.; Laforêt, P.; Maisonobe, T.; Amouri, R.; Haddad, H.J.B. A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C. Brain 2012, 135, 483–492. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Hamdi, Y.; Mighri, N.; Boujemaa, M.; Mejri, N.; Ben Nasr, S.; Ben Rekaya, M.; Messaoud, O.; Bouaziz, H.; Berrazega, Y.; Rachdi, H.; et al. Identification of Eleven Novel BRCA Mutations in Tunisia: Impact on the Clinical Management of BRCA Related Cancers. Front. Oncol. 2021, 11, 674965. [Google Scholar] [CrossRef] [PubMed]
  100. Brosco, J.P.; Grosse, S.D.; Ross, L.F. Universal state newborn screening programs can reduce health disparities. JAMA Pediatr. 2015, 169, 7–8. [Google Scholar] [CrossRef]
  101. Heeju Sohna, S.T. Inequities in newborn screening: Race and the role of medicaid. SSM—Popul. Health 2019, 9, 100496. [Google Scholar] [CrossRef] [PubMed]
  102. Hinton, C.F.; Mai, C.T.; Nabukera, S.K.; Botto, L.D.; Feuchtbaum, L.; Romitti, P.A.; Wang, Y.; Piper, K.N.; Olney, R.S. Developing a public health-tracking system for follow-up of newborn screening metabolic conditions: A four-state pilot project structure and initial findings. Genet. Med. 2014, 16, 484–490. [Google Scholar] [CrossRef] [Green Version]
  103. Urv, T.K.; Parisi, M.A. Newborn Screening: Beyond the Spot. Rare Diseases Epidemiology: Update Overview; Springer: Berlin/Heidelberg, Germany, 2017; pp. 323–346. [Google Scholar] [CrossRef]
  104. Romero, S.; Rink, B.; Biggio, J., Jr. Carrier screening in the age of genomic medicine: ACOG committee opinion, number 690. Obs. Gynecol. 2017, 129, e35–e40. [Google Scholar]
  105. Ben-Shachar, R.; Svenson, A.; Goldberg, J.D.; Muzzey, D. A data-driven evaluation of the size and content of expanded carrier screening panels. Genet. Med. 2019, 21, 1931–1939. [Google Scholar] [CrossRef]
  106. Krotoski, D.; Namaste, S.; Raouf, R.K.; El Nekhely, I.; Hindi-Alexander, M.; Engelson, G.; Hanson, J.W.; Howell, R.R.; Committee, M.N.S. Conference report: Second conference of the Middle East and North Africa newborn screening initiative: Partnerships for sustainable newborn screening infrastructure and research opportunities. Genet. Med. 2009, 11, 663–668. [Google Scholar] [CrossRef] [Green Version]
  107. Teebi, A.S.; El-Shanti, H.I. Consanguinity: Implications for practice, research, and policy. J. Lancet 2006, 367, 970–971. [Google Scholar] [CrossRef]
  108. Hsairi, M.; Mehdi, F.; Bellaaj, R.; Kassis, M.J.L.T. Health screening strategies in Maghreb countries: Situation Analysis and perspectives. Tunis. Med. 2018, 96, 688–695. [Google Scholar] [PubMed]
  109. Mohamed, S.; Elsheikh, W.; Al-Aqeel, A.I.; Alhashem, A.M.; Alodaib, A.; Alahaideb, L.; Almashary, M.; Alharbi, F.; AlMalawi, H.; Ammari, A.; et al. Incidence of newborn screening disorders among 56632 infants in Central Saudi Arabia. A 6-year study. Saudi Med. J. 2020, 41, 703–708. [Google Scholar] [CrossRef] [PubMed]
  110. Abdelmoktader, A.M. Risk factors for congenital hypothyroidism in Egypt: Results of a population case-control study (2003–2010). Ann. Saudi Med. 2013, 33, 273–276. [Google Scholar] [CrossRef] [PubMed]
  111. Sadek, A.A.; Hassan, M.H.; Mohammed, N.A. Clinical and neuropsychological outcomes for children with phenylketonuria in Upper Egypt; a single-center study over 5 years. Neuropsychiatr. Dis. Treat. 2018, 14, 2551–2561. [Google Scholar] [CrossRef] [Green Version]
  112. Sirdah, M.M.; Al-Kahlout, M.S.; Reading, N.S. National G6PD neonatal screening program in Gaza Strip of Palestine: Rationale, challenges and recommendations. Clin. Genet. 2016, 90, 191–198. [Google Scholar] [CrossRef]
  113. Nouaili, E.B.H.; Chaouachi, S.; Bezine, A.; Hamadi, M.; Mbarek, C. Dépistage Systématique de la Surdité en Maternité par Oto-Emissions Acoustiques Provoquées (OTEAP): Etude Pilote. Tunis. Méd. 2010, 88, 482–485. [Google Scholar]
  114. Raz, A.E.; Atar, M. Cousin marriage and premarital carrier matching in a Bedouin community in Israel: Attitudes, service development and educational intervention. BMJ. Sex. Reprod. Health 2004, 30, 49–51. [Google Scholar] [CrossRef] [Green Version]
  115. Shiloh, S.; Reznik, H.; Bat-Miriam-Katznelson, M.; Goldman, B. Pre-marital genetic counselling to consanguineous couples: Attitudes, beliefs and decisions among counselled, noncounselled and unrelated couples in Israel. Soc. Sci. Med. 1995, 41, 1301–1310. [Google Scholar] [CrossRef]
  116. Al Arrayed, S. Campaign to control genetic blood diseases in Bahrain. Public Health Genom. 2005, 8, 52–55. [Google Scholar] [CrossRef]
  117. Al Arrayed, S.; Al Hajeri, A. Public awareness of sickle cell disease in Bahrain. Ann. Saudi Med. 2010, 30, 284–288. [Google Scholar] [CrossRef]
  118. Zitouna, N.; Zekri, L.A.; Wardi, N.; Marrakchi, J.; Bouattour, Y.; Ben Hassine, H. Setting-up of a Science Shop project on the early detection of hearing impairment among preschool and school children. In Proceedings of the Inaugural Meeting of the Hearing Institute, Collège de France, Paris, France, 16–17 September 2019. [Google Scholar]
Genes 12 01820 g001 550
Figure 1. Screening process workflow.
Figure 1. Screening process workflow.
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Figure 2. WHO ICD-10 classification of genetic diseases.
Figure 2. WHO ICD-10 classification of genetic diseases.
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Figure 3. Classification according to the inheritance mode of the whole spectrum of genetic disorders (AR: Autosomal Recessive; AD: Autosomal Dominant; XL: X-linked; Spo: Sporadic; Mito: Mitochondrial; YL: Y-linked).
Figure 3. Classification according to the inheritance mode of the whole spectrum of genetic disorders (AR: Autosomal Recessive; AD: Autosomal Dominant; XL: X-linked; Spo: Sporadic; Mito: Mitochondrial; YL: Y-linked).
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Table
Table 1. Diseases with an identified molecular etiology determined in the last decade.
Table 1. Diseases with an identified molecular etiology determined in the last decade.
Disease NameOMIMInheritanceGene (OMIM)Genetic Variant(s)ICD-10 ClassificationApproach Used for Molecular DiagnosisReferences
Adrenal Hyperplasia, Congenital, due to 11-β-Hydroxylase Deficiency202010ARCYP11B1 (610613)c.1066C > T (p.Gln356Ter)Endocrine, nutritional, and metabolic diseasesSanger sequencing[24]
c.1136G > T (p.Gly379Val)
Adrenoleukodystrophy300100XLABCD1 (300371)c.284C > A (p.Ala95Asp)Endocrine, nutritional, and metabolic diseasesSanger sequencing[25]
Alstrom syndrome203800ARALMS 1 (606844)c.10388-2A > GCongenital malformations, deformations, and chromosomal abnormalitiesTargeted Gene sequencing[26]
Bloom syndrome210900ARBLM (604610)c.1980-1982delAA (p.Lys662fsX5)Congenital malformations, deformations, and chromosomal abnormalitiesSanger sequencingEzzine et al., Unpublished
[27]
FVII deficiency227500ARF7 (613878)c.90-91insA (p.12LeufsX11)Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanismSanger sequencing[28]
c.592 T > C (p.Cys198Arg)
c.1615 G > C (p.Gly539Arg)
c.2409 T > C (p.Asn784Asn)
c.2167 G > A (p.Ala704Thr)
c.3870-3871insA (p.1271LysfsX29)
c.1696 C > T (p.Leu547Phe)
c.1492 G > A (p.Gly479Arg)
c.77 T > C (p.Leu7Pro)
c.5071-5075delATGAA (p.1671-3fsX)
c.3637-3638delA (p.1191IlefsX5)
c.6873-6876delTC (p.2272ThrfsX)
c.4379-4380insA (p.1441LysfsX2)
c.3637-3638insA (p.1191LeufsX29)
c.2236-2237insT (p.727SerfsTer)
Gaucher disease type III A231000ARGBA (606463)c.1109T > C (p.Phe370Ser)Endocrine, nutritional, and metabolic diseasesSanger sequencing[29]
c.1330_1331delGAinsCC
(p.Asp444Pro)
Junctional epidermolysis bullosa (JEB) Herlitz type226700ARLAMA3
(600805)		c.2865C > G (p.His955Gln)Congenital malformations, deformations, and chromosomal abnormalitiesSanger sequencing[30]
Lafora disease254780AREPM2A (607566)c.659 T > A (p.Leu220Gln)Diseases of the nervous systemSanger sequencing[31]
Lysosomal acid lipase deficiency278000ARLIPA (613497)c.153 C > A (p.Tyr51Ter)Endocrine, nutritional, and metabolic diseasesSanger sequencing[32]
Maple syrup urine disease, type Ib248600
ARBCKDHB (248611)c.716A > G (p.Glu239Gly)Endocrine, nutritional, and metabolic diseasesSanger sequencing[33]
Meckel syndrome type 2603194ARTMEM216(613277)c.341T > G (p.Leu114Arg)Congenital malformations, deformations, and chromosomal abnormalitiesExome sequencing[34]
MELAS syndrome540000MitochondrialMT-TV (590105)m.1640A > GDiseases of the nervous systemSanger sequencing[35]
Microphthalmia isolated, 6613517ARPRSS56 (613858)c.1059_1066insC (p.Gln356ProfsTer152)Congenital malformations, deformations, and chromosomal abnormalitiesSanger sequencing[36]
Miyoshi muscular dystrophy 1254130ARDYSF (603009)c.4597-2A > GDiseases of the nervous systemTargeted Gene Sequencing[37]
Mucopolysaccharidosis type II309900XLIDS (300823)c.240 + 1 G > AEndocrine, nutritional, and metabolic diseasesSanger sequencing[38]
c.263G > A (p.Arg88Pro)
c.610C > T (p.Gln204Ter)
c.1348G > A (Asp450Asn)
c.281G > A (p.Gly94Asp)
c.1186C > T (p.Gln396Ter)
Mucopolysaccharidosis type IIIA252900ARSGSH (605270)c.2t > C (p.Met1Thr)Endocrine, nutritional, and metabolic diseasesSanger sequencing[39]
c.1129C > T (p.Arg377Cys)
g.75802301_75809393del
c.1093C > T (p.Gln365Ter)
c.29dup (p.Leu11AlafsTer22)
c.197C > G (p.Ser66Trp)
c.1080del (p.Val361SerfsTer52)
Mucopolysaccharidosis type IIIB252920ARNAGLU (60970)c.1674C > G (p.Tyr558X)Endocrine, nutritional, and metabolic diseasesSanger sequencing[39]
c.1811C > T (p.Pro604Leu)
Mucopolysaccharidosis type IIIC252930ARHGSNAT (610453)c.1209G > A (p.Trp403X)Endocrine, nutritional, and metabolic diseasesSanger sequencing[39]
c.1880A > G (p.Tyr627Cys)
Myoclonic epilepsy of Lafora254780AREPM2A (607566)c.659 T > A (p.Leu220Gln)Diseases of the nervous
System		Sanger sequencing[31]
Nephropathic cystinosis219800ARCTNS (606272)c.1515G > A (p.Gly308Arg)Endocrine, nutritional, and metabolic diseasesSanger sequencing[40]
c.771_793del (p.Gly258SerfsTer30)
Punctate palmoplantar keratoderma type 1148600ADAAGAB (614888)c.481C > T (p.Arg161Ter)Congenital malformations, deformations, and chromosomal abnormalitiesWhole exome sequencing[41]
AR: Autosomal Recessive; AD: Autosomal Dominant; XL: X-linked; Mito: Mitochondrial.
Table
Table 2. Comorbid associations described among Tunisians between 2016 and 2020.
Table 2. Comorbid associations described among Tunisians between 2016 and 2020.
AssociationsFamilial/IndividualInheritanceConsanguinityReferences
Allgrove syndrome—Hearing lossFamilialAR—ARYesMkaouar et al., unpublished
Amyotrophic lateral sclerosis—Behcet’s diseaseIndividualAD, AR—UnknownNA[43]
Autism—Hearing lossFamilialComplex heredity—ARYesLahbib et al., unpublished
Cutis laxa—Pulmonary diseaseFamilialUnknown-UnknownNATinsa et al., unpublished
Growth hormone deficiency—ImmunodeficiencyIndividualUnknown-UnknownNATinsa et al., unpublished
Ichthyosis congenital autosomal recessive 1—Erythrokeratodermia variabilisFamilialAR—ADNoLaroussi et al., Unpublished
Ichthyosis congenital autosomal recessive 5—hearing lossIndividualAR—ARYes[44]
Ichthyosis congenital autosomal recessive 1-Muscular dystrophy limb girdle type 2AIndividualAR-ARYesMezzi et al., Unpublished
Incontinentia pigmenti—Noonan syndromeIndividualXLD—ADNo[45]
Maternally inherited diabetes—deafness-RetinopathyIndividualMitochondrial—UnknownNo[46]
Niemann-Pick disease type B—Systemic lupus erythematousFamilialAR—ADNo[47]
Pernicious anemia—PseudohypoparathyroidismIndividualUnknown-UnknownNATinsa et al., unpublished
Xeroderma pigmentosum group A—Autoimmune polyendocrinopathy syndrome IIndividualAR—AR, ADYesMessaoud et al., Unpublished
Xeroderma pigmentosum group C—Rothmund Thomson syndromeFamilialAR—ARYesEzzine et al., Unpublished
AR: Autosomal Recessive; AD: Autosomal Dominant; XLD: X-linked Dominant; Mito: Mitochondrial.
Table
Table 3. Genetic diseases with unusual clinical findings among Tunisians.
Table 3. Genetic diseases with unusual clinical findings among Tunisians.
DiseasesUnusual Clinical FindingsCase countReferences
Chanarin-Dorfman syndrome Thyroid function impairment7[48]
Palmoplantar keratoderma Abnormal cornification and a diffuse yellowish keratoderma with the characteristic skin thickening1[49]
Juvenile Parkinson disease No evidence of sleep or autonomic dysfunctions and psychiatric disorders in both patients1[50]
Table
Table 4. Genetic diseases with available epidemiological data among Tunisians.
Table 4. Genetic diseases with available epidemiological data among Tunisians.
Genetic Disease (MIM)FrequencyReferencesMeasure of EstimationState/Region/GroupPrevalence in Orphanet **
Anemia, Nonspherocytic hemolytic, due to G6PD deficiency (ANH- G6PD)
(300908)		18,400/million/year[51]IncidenceAll across Tunisia<1/1,000,000
β thalassemia ( β -thal) (613985) 44.2/2000[52]PrevalenceAll across Tunisia1–9/1,000,000
Creutzleldt-Jakob Disease (CJD*) (123400) 2.3/million/year[53]IncidenceAmong Tunisian Jews<1/1,000,000
Cystic fibrosis (CF*) (219700) 1.5 new cases/year
0.4/1000		[54]Incidence
Prevalence		In the Pediatric department B of the Children’s Hospital Béchir Hamza de Tunis (among patients’ series)
Most from the north and the south of Tunisia		NA
0.4/1000
Its prevalence was 0.4 per 1000 hospitalizations.		1–9/100,000
Dermatitis, Atopic (ATOD) (603165) 451 cases during a 7 years period[55]IncidenceAll across TunisiaNA
Epidermolysis bullosa dystrophica Hallopeau-Simens type 1 (RDEB*) (226600) 2.3/2000Cherif et al., 2005 unpublishedPrevalenceAll across Tunisia<1/1,000,000
0.1/2000[56]In the governorate of Sfax
Exfoliation syndrome (XFS) (177650) 220/2000[57]PrevalenceAll across TunisiaNA
Familial Adenomatous polyposis of the colon (FAP1) (MIM: 175100) 74/million/year[58]IncidenceAll across Tunisia1–9/100,000
Fanconi anemia (FA)
(227650)		1.4/million/year[59]IncidenceAll across Tunisia1/160,000
Familial hypercholesterolemia, (FHCL*) 12.12/2000[60]PrevalenceIn central and southern Tunisia1–9/1,000,000
Gaucher disease, type I (GD1) (230800) 0.0096/2000 [61]PrevalenceAll across Tunisia1/100,000
Glycine encephalopathy (GCE*) (605899) 1/9322[62]IncidenceIn the governorate of Kairouan1–9/1,000,000
Glycogen storage disease type Ia (GSD1A*) (232200) 0.02/2000[63]PrevalenceIn the north of TunisiaNA
7.93/million/yearIncidence1/100,000 (Incidence)
Hemoglobinopathies 89.6/2000 [52]PrevalenceAll across TunisiaNA
Hurler syndrome (HS*) (607014) 0.064/2000[64]PrevalenceIn Tunisian Jews1/200,000
Limb-girdle Muscular dystrophytype 2C (LGMD2C) (253700) 0.6/2000[65]PrevalenceAll across Tunisia1–9/1,000,000
Lynch syndrome 1 (LS1) (120435) 70/million/year [66]IncidenceAll across TunisiaNA
Megaloblastic anemia 1 (MGA1*) (261100) 2/2000[67]PrevalenceIn Tunisian JewsNA
Mucopolysaccharidosis I (MPS1-S) (607016) 0.0126/2000[59]PrevalenceAll across Tunisia1/100,000
Mucopolysaccharidosis type IIIA (MPS 3A) (252900) 0.007/2000[59]PrevalenceAll across Tunisia1–9/100,000
Mucopolysaccharidosis type IVA (MPS4A) (253000) 0.025/2000[68]PrevalenceAll across Tunisia1–5/10,000
Mucopolysaccharidosis type VI (MPS 6) (253200) 0.013/2000[62]PrevalenceAll across Tunisia1–9/1,000,000
Niemann Pick disease B (607616) 0.1/2000 [66]Prevalence 1–9/1,000,000
Phenylketonuria (PKU) (261600) Varies between 0.29/2000 and 0.6/2000[67]PrevalenceAll across Tunisia1–5/10,000
Sickle Cell Anemia (SCA) (603903) 37.8/2000[52]PrevalenceAll across Tunisia1/150
Xeroderma pigmentosum , complementation group A (XPA) (278700) 0.2/2000 [69]PrevalenceAll across Tunisia1/1,000,000
AD: Autosomal dominant, AR: Autosomal recessive, XLD: X-linked dominant. * Diseases with prevalence and/or incidence among a specific ethnic group or in specific regions. ** (https://www.orpha.net/, accessed on 27 September 2021).
Table
Table 5. Screening of genetic diseases in Tunisia.
Table 5. Screening of genetic diseases in Tunisia.
Diseases (MIM)Screening TypeScreening TechniquesCountry CoverageReferences
α-thalassemia Prenatal screeningDNA analysis from amniotic fluidBiochemistry and molecular biology department in children’s hospital of Tunis (pilot study)[70]
β-thalassemia Prenatal screening
Carrier screening		DNA analysis from amniotic fluid
Screening for mutations described in Tunisians		Biochemistry and molecular biology department in children’s hospital of Tunis (pilot study)[70]
Congenital hypothyroidism Newborn screeningTSH and T4 radioimmunoassay
on drops of blood		Maternity and Neonatal Centre in Tunis (pilot study)Elkadri et al. *
Cystic fibrosis Prenatal screeningGenetic analysis by denaturant gradient gel electrophoresis and denaturing high-pressure liquid phase chromatographyBiochemistry Laboratory, Bechir Hamza Children’s hospital in Tunis
Center of maternity and neonatology, in Tunis
(pilot study)		[71]
Hearing impairment Newborn screeningEvoked otoacoustic emissions (EOAE) and auditory brain stem response (ABR)Charles Nicolle hospital of Tunis ((pilot study)
Regional hospital in Nabeul (pilot study)
Regional hospital in Sfax (systematic)		[72]
Feedback from collaborating clinician
G6PD deficiency Newborn screeningDosage of the enzymatic activity using spectrophotometric methodMaternity and Neonatal Centre in Tunis (pilot study)[73]
Phenylketonuria Newborn screeningDosage of phenylalanine in dried blood spotsHospital of La Rabta in Tunis
(pilot study)		[68]
Sickle cell disease Newborn screeningIsoelectrofocusingMaternity Centre of Aziza Othmana Hospital and Neonatal and Maternity Centre—La Rabta in Tunis
(pilot study)		[74]
* Available online: http://docplayer.fr/66862824-Depistage-de-l-hypothyroidie-congenitale-a-tunis-seuils-de-rappel-et-protocole.html (accessed on 27 September 2021).
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MDPI and ACS Style

Mezzi, N.; Messaoud, O.; Mkaouar, R.; Zitouna, N.; Romdhane, S.; Abdessalem, G.; Charfeddine, C.; Maazoul, F.; Ouerteni, I.; Hamdi, Y.; et al. Spectrum of Genetic Diseases in Tunisia: Current Situation and Main Milestones Achieved. Genes 2021, 12, 1820. https://doi.org/10.3390/genes12111820

AMA Style

Mezzi N, Messaoud O, Mkaouar R, Zitouna N, Romdhane S, Abdessalem G, Charfeddine C, Maazoul F, Ouerteni I, Hamdi Y, et al. Spectrum of Genetic Diseases in Tunisia: Current Situation and Main Milestones Achieved. Genes. 2021; 12(11):1820. https://doi.org/10.3390/genes12111820

Chicago/Turabian Style

Mezzi, Nessrine, Olfa Messaoud, Rahma Mkaouar, Nadia Zitouna, Safa Romdhane, Ghaith Abdessalem, Cherine Charfeddine, Faouzi Maazoul, Ines Ouerteni, Yosr Hamdi, and et al. 2021. "Spectrum of Genetic Diseases in Tunisia: Current Situation and Main Milestones Achieved" Genes 12, no. 11: 1820. https://doi.org/10.3390/genes12111820

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