Consanguinty and its impact on health and genome dynamic: An example from Tunisia.

The genetic disease spectrum in Tunisia arises from the founder effect, genetic drift, selection, and consanguinity. The latter represents a deviation from panmixia, characterized by a non-random matrimonial choice that may be subject to several rules, such as socio-cultural, economic, or other factors. This shifts the genetic structure away from the Hardy-Weinberg equilibrium, increasing homozygous genotypes and decreasing heterozygotes, thus raising the frequency of autosomal recessive diseases. Similar to other Arab populations, Tunisia displays high consanguinity rates that vary geographically. Approximately 60% of reported diseases in Tunisia are autosomal recessive, with consanguinity possibly occurring in 80% of families for a specific disease. In inbred populations, consanguinity amplifies autosomal recessive disease risk, yet it does not influence autosomal dominant disease likelihood but rather impacts its phenotype. Consanguinity is also suggested to be a major factor in the homozygosity of deleterious variants leading to comorbid expression. At the genome level, inbred individuals inherit homozygous mutations and adjacent genomic regions known as runs of homozygosity (ROHs). Short ROHs indicate distant inbreeding, while long ROHs refer to recent inbreeding. ROHs are distributed rather irregularly across the genome, with certain short regions featuring an excess of ROH, known as ROH islands. In this review, we discuss consanguinity's impact on population health and genome dynamics, using Tunisia as a model.

Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health.

Hearing impairment (HI) is a prevalent neurosensory condition globally, impacting 5% of the population, with over 50% of congenital cases attributed to genetic etiologies. In Tunisia, HI underdiagnosis prevails, primarily due to limited access to comprehensive clinical tools, particularly for syndromic deafness (SD), characterized by clinical and genetic heterogeneity. This study aimed to uncover the SD spectrum through a 14-year investigation of a Tunisian cohort encompassing over 700 patients from four referral centers (2007-2021). Employing Sanger sequencing, Targeted Panel Gene Sequencing, and Whole Exome Sequencing, genetic analysis in 30 SD patients identified diagnoses such as Usher syndrome, Waardenburg syndrome, cranio-facial-hand-deafness syndrome, and H syndrome. This latter is a rare genodermatosis characterized by HI, hyperpigmentation, hypertrichosis, and systemic manifestations. A meta-analysis integrating our findings with existing data revealed that nearly 50% of Tunisian SD cases corresponded to rare inherited metabolic disorders. Distinguishing between non-syndromic and syndromic HI poses a challenge, where the age of onset and progression of features significantly impact accurate diagnoses. Despite advancements in local genetic characterization capabilities, certain ultra-rare forms of SD remain underdiagnosed. This research contributes critical insights to inform molecular diagnosis approaches for SD in Tunisia and the broader North-African region, thereby facilitating informed decision-making in clinical practice.

Ethnic and functional differentiation of copy number polymorphisms in Tunisian and HapMap population unveils insights on genome organizational plasticity.

Admixture mapping has been useful in identifying genetic variations linked to phenotypes, adaptation and diseases. Copy number variations (CNVs) represents genomic structural variants spanning large regions of chromosomes reaching several megabases. In this investigation, the "Canary" algorithm was applied to 102 Tunisian samples and 991 individuals from eleven HapMap III populations to genotype 1279 copy number polymorphisms (CNPs). In this present work, we investigate the Tunisian population structure using the CNP makers previously identified among Tunisian. The study revealed that Sub-Saharan African populations exhibited the highest diversity with the highest proportions of allelic CNPs. Among all the African populations, Tunisia showed the least diversity. Individual ancestry proportions computed using STRUCTURE analysis revealed a major European component among Tunisians with lesser contribution from Sub-Saharan Africa and Asia. Population structure analysis indicated the genetic proximity with Europeans and noticeable distance from the Sub-Saharan African and East Asian clusters. Seven genes harbouring Tunisian high-frequent CNPs were identified known to be associated with 9 Mendelian diseases and/or phenotypes. Functional annotation of genes under selection highlighted a noteworthy enrichment of biological processes to receptor pathway and activity as well as glutathione metabolism. Additionally, pathways of potential concern for health such as drug metabolism, infectious diseases and cancers exhibited significant enrichment. The distinctive genetic makeup of the Tunisians might have been influenced by various factors including natural selection and genetic drift, resulting in the development of distinct genetic variations playing roles in specific biological processes. Our research provides a justification for focusing on the exclusive genome organization of this population and uncovers previously overlooked elements of the genome.

Comorbidity of bathing suit ichthyosis and limb-girdle muscular dystrophy type 2 A in a Tunisian patient revealed by Whole Exome Sequencing.

Elevated rates of consanguinity and inbreeding are responsible for the high prevalence of recessively inherited diseases among inbred populations including Tunisia. In addition, the co-occurrence of two of these conditions, called also comorbidity, within the same individual or in members of the same family are often described in Tunisia which is challenging for diagnosis. The high throughput sequencing has improved the diagnosis of inherited diseases. We report here on a 32-year-old woman born to consanguineous parents. She presented with congenital ichthyosis and muscular dystrophy. She was primarily suspected as suffering from Chanarin-Dorfman syndrome (CDS) with unusual form. Screening of founder mutations allowed only the elucidation of the molecular etiology of Ichthyosis. As the result was inconclusive, Whole Exome Sequencing (WES) was conducted. WES data analysis led to the identification of a mutation in the CAPN3 gene underlying limb-girdle muscular dystrophy type 2A (LGMD2A). Sanger sequencing confirmed the familial segregation of mutations. This work presents the first case worldwide of individual comorbidity of bathing suit ichthyosis and LGMD2A. The co-occurrence of two diseases should be systematically considered when establishing a diagnosis especially in consanguineous populations. WES is a powerful tool for molecular diagnosis in particular for revealing comorbidities and rectifying the diagnosis.

African Genomic Medicine Portal: A Web Portal for Biomedical Applications.

Genomics data are currently being produced at unprecedented rates, resulting in increased knowledge discovery and submission to public data repositories. Despite these advances, genomic information on African-ancestry populations remains significantly low compared with European- and Asian-ancestry populations. This information is typically segmented across several different biomedical data repositories, which often lack sufficient fine-grained structure and annotation to account for the diversity of African populations, leading to many challenges related to the retrieval, representation and findability of such information. To overcome these challenges, we developed the African Genomic Medicine Portal (AGMP), a database that contains metadata on genomic medicine studies conducted on African-ancestry populations. The metadata is curated from two public databases related to genomic medicine, PharmGKB and DisGeNET. The metadata retrieved from these source databases were limited to genomic variants that were associated with disease aetiology or treatment in the context of African-ancestry populations. Over 2000 variants relevant to populations of African ancestry were retrieved. Subsequently, domain experts curated and annotated additional information associated with the studies that reported the variants, including geographical origin, ethnolinguistic group, level of association significance and other relevant study information, such as study design and sample size, where available. The AGMP functions as a dedicated resource through which to access African-specific information on genomics as applied to health research, through querying variants, genes, diseases and drugs. The portal and its corresponding technical documentation, implementation code and content are publicly available.

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

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.

A map of copy number variations in the Tunisian population: a valuable tool for medical genomics in North Africa.

Copy number variation (CNV) is considered as the most frequent type of structural variation in the human genome. Some CNVs can act on human phenotype diversity, encompassing rare Mendelian diseases and genomic disorders. The North African populations remain underrepresented in public genetic databases in terms of single-nucleotide variants as well as for larger genomic mutations. In this study, we present the first CNV map for a North African population using the Affymetrix Genome-Wide SNP (single-nucleotide polymorphism) array 6.0 array genotyping intensity data to call CNVs in 102 Tunisian healthy individuals. Two softwares, PennCNV and Birdsuite, were used to call CNVs in order to provide reliable data. Subsequent bioinformatic analyses were performed to explore their features and patterns. The CNV map of the Tunisian population includes 1083 CNVs spanning 61.443 Mb of the genome. The CNV length ranged from 1.017 kb to 2.074 Mb with an average of 56.734 kb. Deletions represent 57.43% of the identified CNVs, while duplications and the mixed loci are less represented. One hundred and three genes disrupted by CNVs are reported to cause 155 Mendelian diseases/phenotypes. Drug response genes were also reported to be affected by CNVs. Data on genes overlapped by deletions and duplications segments and the sequence properties in and around them also provided insights into the functional and health impacts of CNVs. These findings represent valuable clues to genetic diversity and personalized medicine in the Tunisian population as well as in the ethnically similar populations from North Africa.

Consanguinity and Inbreeding in Health and Disease in North African Populations.

North Africa is defined as the geographical region separated from the rest of the continent by the Sahara and from Europe by the Mediterranean Sea. The main demographic features of North African populations are their familial structure and high rates of familial and geographic endogamy, which have a proven impact on health, particularly the occurrence of genetic diseases, with a greater effect on the frequency and spectrum of the rarest forms of autosomal recessive genetic diseases. More than 500 different genetic diseases have been reported in this region, most of which are autosomal recessive. During the last few decades, there has been great interest in the molecular investigation of large consanguineous North African families. The development of local capacities has brought a substantial improvement in the molecular characterization of these diseases, but the genetic bases of half of them remain unknown. Diseases of known molecular etiology are characterized by their genetic and mutational heterogeneity, although some founder mutations are encountered relatively frequently. Some founder mutations are specific to a single country or a specific ethnic or geographic group, and others are shared by all North African countries or worldwide. The impact of consanguinity on common multifactorial diseases is less evident.