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

Mezzi, Nessrine; Messaoud, Olfa; Mkaouar, Rahma; Zitouna, Nadia; Romdhane, Safa; Abdessalem, Ghaith; Charfeddine, Chérine; Mâazoul, Faouzi; Ouerteni, Ines; Hamdi, Yosr; Zaouak, Anissa; Mrad, Ridha; Abdelhak, Sonia; Romdhane, Lilia

doi:10.3390/genes12111820

Cited by 9 publications

(5 citation statements)

References 100 publications

(94 reference statements)

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“…These findings could be explained by the significant variability in GC frequency worldwide as well as risk factors [ 1 ]. Our findings highlight the particular genetic background of the Tunisian population compared to others [ 55 , 56 , 57 , 58 , 59 ].…”

Section: Discussionsupporting

confidence: 56%

CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma

Aissa-Haj

Kabbage

Othman

et al. 2022

Genes

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Mutational screening of the CDH1 gene is a standard treatment for patients who fulfill Hereditary Diffuse Gastric Cancer (HDGC) testing criteria. In this framework, the classification of variants found in this gene is a crucial step for the clinical management of patients at high risk for HDGC. The aim of our study was to identify CDH1 as well as CTNNA1 mutational profiles predisposing to HDGC in Tunisia. Thirty-four cases were included for this purpose. We performed Sanger sequencing for the entire coding region of both genes and MLPA (Multiplex Ligation Probe Amplification) assays to investigate large rearrangements of the CDH1 gene. As a result, three cases, all with the HDGC inclusion criteria (8.82% of the entire cohort), carried pathogenic and likely pathogenic variants of the CDH1 gene. These variants involve a novel splicing alteration, a missense c.2281G > A detected by Sanger sequencing, and a large rearrangement detected by MLPA. No pathogenic CTNNA1 variants were found. The large rearrangement is clearly pathogenic, implicating a large deletion of two exons. The novel splicing variant creates a cryptic site. The missense variant is a VUS (Variant with Uncertain Significance). With ACMG (American College of Medical Genetics and Genomics) classification and the evidence available, we thus suggest a revision of its status to likely pathogenic. Further functional studies or cosegregation analysis should be performed to confirm its pathogenicity. In addition, molecular exploration will be needed to understand the etiology of the other CDH1- and CTNNA1-negative cases fulfilling the HDGC inclusion criteria.

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Section: Discussionsupporting

confidence: 56%

CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma

Aissa-Haj

Kabbage

Othman

et al. 2022

Genes

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“…Articles reporting either clinical descriptions, genetic studies or both were captured. We also referred to the local genetic diseases database, developed at the LGBMO and gathering 589 entities ( Mezzi et al, 2021 ), in order to retrieve genetic conditions associated with HI. Grey literature sources included medical and scientific dissertations or theses, abstracts and posters presented in national and international conferences as well as those found in websites and specialized databases.…”

Section: Methodsmentioning

confidence: 99%

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

Mkaouar,

Riahi,

Marrakchi

et al. 2024

Front. Genet.

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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.

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“…These results are based on advancements in molecular genetic testing for ATS, and studies that estimated the frequencies of COL4A3, COL4A4, and COL4A5 PVs in sequencing databases of populations but without known neither kidney disease nor adjusting for the disease penetrance of individual variants [19][20][21]. In our population, this difference in transmission patterns can be attributed to the high rate of consanguinity in Tunisian families [22]. The high inbreeding rate in the studied sample further supports this characteristic of the population: 6 out of 11 families compared to 1 out of 3 families in the Tunisian population.…”

Section: Discussionmentioning

confidence: 89%

Inversion of the Frequencies of Autosomal Recessive and X-Linked Dominant Forms of Alport Syndrome in the Tunisian Population

Mariem,

Achour,

Kraoua

et al. 2023

Preprint

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Background: Alport syndrome is defined by the co-occurrence of hematuria, renal failure, and a family history of renal failure or hematuria. Pathogenic variants in COL4A3, COL4A4, and COL4A5 cause this phenotype. These genes code for the α3, α4, and α5 chains of collagen IV found in the kidneys, eyes, and cochlea. This explains the frequent association of extra-renal signs, such as bilateral sensorineural deafness and ocular abnormalities. Different modes of transmission have been reported. X-linked transmission is attributed to the pathogenic variants of COL4A5, while homozygous pathogenic variants of COL4A3 or COL4A4 lead to autosomal recessive inheritance. The digenic form occurs when a pathological variation in both COL4A3 and COL4A4coexist. Additionally, autosomal dominant inheritance can occur due to heterozygous pathogenic variants in COL4A3or COL4A4. In this study, we investigated 45 patients with Alport syndrome from 11 Tunisian families to establish their clinical and genetic characteristics. Methods: Clinical data were collected retrospectively, and molecular analysis of COL4A3, A4,andA5 was performed. Among the 45 patients, whole-exome sequencing was performed on 11 individuals, with one patient selected from each family. All candidate pathogenic variations were validated by Sanger sequencing. Cascade screening in the family of each proband allowed us to expand the number of individuals tested to 53 to verify the presence of the pathogenic variant found in their family. Results: We identified 9 likely pathogenic variations among 11 index cases. Six were novel variations and three were known ones. Of these, five out of nine were in the COL4A3 gene, while four out of nine were found in the COL4A5 gene. Frame-shift, nonsense, missense, and alternative splicing variants were detected in our cohort. Most of these variants affected the Gly-XY codon.Thirty out of the 45 clinically identified siblings were tested and confirmed for Alport syndrome. Cascade screening then identified 3 additional affected individuals, along with 10 unaffected siblings and 10 unaffected parents.The mode of inheritance of Alport syndrome was autosomal recessive in 6 familiesand X-linked in 4 families. Conclusions: This study represents the first Tunisian screening of the mutational spectrum of Alport syndrome. It contributes new pathogenic variants to the literature and demonstrates that autosomal recessive inheritance of Alport syndrome is more frequent in the Tunisian population than the X-linked dominant form as reported in the literature.

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

Cited by 9 publications

References 100 publications

CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma

CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma

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

Inversion of the Frequencies of Autosomal Recessive and X-Linked Dominant Forms of Alport Syndrome in the Tunisian Population

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