Specific Aspects of Consanguinity: Some Examples from the Tunisian Population

Romdhane, Lilia; Rejeb, Imen; Kéfi, Rym; Bouyacoub, Yosra; Rekaya, Mariem Ben; Messai, Habib; Messaoud, Olfa; Riahi, Zied; Bonnet, Crystel; Rhouma, Faten Ben; Nagara, Majdi; Petit, Christine; McElreavey, Ken; Romeo, Giovanni; Abdelhak, Sonia

doi:10.1159/000362167

Cited by 18 publications

(21 citation statements)

References 38 publications

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“…This high rate of consanguineous marriages in the Tunisian population has been estimated to increase sixfold the risk of an autosomal recessive disease. 31,32 Taking into account all these ascertainments, we assume that H syndrome may be underdiagnosed and we suspect that it could be even greater in Tunisia and in regions of the world where a high rate of consanguinity is noted. The reasons for underdiagnosis of H syndrome may be as follows: (i) patients with mild phenotype (subtle hyperpigmentation only for example) do not seek consultation; (ii) the lack of awareness of clinicians about H syndrome delays accurate diagnosis; and (iii) the small number of university hospitals in the internal regions of Tunisia is a major obstacle for families with limited financial resources.…”

Section: Discussionmentioning

confidence: 99%

H syndrome: Clinical, histological and genetic investigation in Tunisian patients

Jaouadi

Zaouak

Sellami

et al. 2018

The Journal of Dermatology

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H syndrome is a rare autosomal recessive disorder with characteristic dermatological findings consisting of hyperpigmentation and hypertrichosis patches mainly located on the inner thighs and multisystemic involvement including hepatosplenomegaly, hearing loss, heart abnormalities and hypogonadism. The aim of this study was to conduct a clinical and genetic investigation in five unrelated Tunisian patients with suspected H syndrome. Hence, genetic analysis of the SLC29A3 gene was performed for four patients with a clinical diagnosis of H syndrome. We identified a novel frame-shift mutation in the SLC29A3 gene in a female patient with a severe clinical presentation. Furthermore, we report two mutations previously described, the p.R363Q mutation in a male patient and the p.P324L mutation in two patients of different age and sex. This paper extends the mutation spectrum of H syndrome by reporting a novel frame-shift mutation, the p.S15Pfs*86 in exon 2 of SLC29A3 gene and emphasizes the relevance of genetic testing for its considerable implications in early diagnosis and clinical management.

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Section: Discussionmentioning

confidence: 99%

H syndrome: Clinical, histological and genetic investigation in Tunisian patients

Jaouadi

Zaouak

Sellami

et al. 2018

The Journal of Dermatology

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“…The fact that the frequency of consanguineous marriage in Arab countries including Tunisia is very high leads to an increase of the expression of autosomal recessive diseases (33)(34)(35). HGPPS seems to be another example, as all patients come from consanguineous marriage.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Heterogeneity in Six Tunisian Families With Horizontal Gaze Palsy With Progressive Scoliosis: A Retrospective Study of 13 Cases

et al. 2020

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Background: Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) is a rare autosomal recessive congenital disorder characterized by the absence of conjugate horizontal eye movements, and progressive debilitating scoliosis during childhood and adolescence. HGPPS is associated with mutations of the ROBO3 gene. In this study, the objective is to identify pathogenic variants in a cohort of Tunisian patients with HGPPS and to further define ROBO3 genotype-phenotype correlations. Methods: Thirteen Tunisian patients from six unrelated consanguineous families all manifesting HGPPS were genetically investigated. We searched for the causative variants for HGPPS using classical Sanger and whole exome sequencing. Results: Four distinct homozygous mutations were identified in ROBO3 gene. Two of these were newly identified homozygous and non-synonymous mutations, causing effectively damage to the protein by in silico analysis. The other two mutations were previously reported in Tunisian patients with HGPPS. Mutations were validated by Sanger sequencing in parents and affected individuals. Conclusion: To the best of our knowledge, this is the largest ever reported cohort on families with HGPPS in whom ROBO3 mutations were identified. These molecular findings have expanded our knowledge of the ROBO3 mutational spectrum. The relevance of our current study is twofold ; first to assist proper management of the scoliosis and second to protect families at risk.

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“…Combination of rare pathogen variants in DNA repair genes with high or low penetrant variants in BRCA genes among Tunisian breast cancer cases might explain the relatively young onset age and the aggressive tumor types observed in some cases described in local epidemiological reports. Our previous studies have shown a relatively high rate of consanguinity 74,75 that increases the frequency of monogenic diseases such autosomal recessive DNA repair disorders predisposing to cancer and raise the prevalence of healthy carriers 76,77 ; (Ben Rekaya unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing reveals a combination of rare high and low penetrance variants that correlates with familial breast cancer relative risk

Rekaya

Hamdi

Benna

et al. 2020

Preprint

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Background: Genetic risk factors of breast cancer are very heterogeneous and complex. They vary according to the familial relative risk, the age of cancer diagnosis of the index case and the age of the affected relatives.Objectives: We aimed to investigate and identify simultaneously all rare pathogenic and common variants in unrelated BC cases with different relative risk ratios for breast cancer and evaluate the contribution of these variants in genetic susceptibility to breast cancer.Patients and Methods: All frequent mutations in BRCA genes previously identified in Tunisia have been excluded by Sanger sequencing in 42 women affected with high family risk having at least 3 cancer affected related individuals. Two unrelated cases having two different family histories (in terms of different numbers of affected first-degree relatives and young age onset) have been selected for whole exome sequencing. The first family is composed of three sisters F1.1, F1.2 and F1.3 affected at 46, 50, and 32 years old, respectively. The second has only two breast cancer cases, F2.2 and F2.4, affected at late age 61 and 70 years old, respectively, in addition to other 5 members affected by different kinds of cancer. Selected high risk variants were confirmed and segregation analysis was performed using Sanger sequencing. Results and discussion: For F1.1 case, we identified a pathogenic frame-shift loss of function variant in BRCA2 p.Val1283Lysfs. For F2.2 we identified a pathogenic rare variant in OGG1, p.Arg46Gln that co-segregates with a rare non sense variant in BRCA2 p.K3326X, only in the breast cancer affected cases. Moreover, F2.2 patient has 9 other common low penetrant variants in different loci known to represent independently minor, but cumulatively significant, increased risk for breast cancer.Conclusion: Family history and the young age at onset for patient F1.1 correlate with the presence of a rare high penetrant variant (p.Val1283Lysfs) in BRCA2 gene. However, the late age at onset and the less severe phenotype for patient F2.2 are probably the consequence of the presence of a pathogenic variant p.Arg46Gln in OGG1 gene that co-segregate with a low penetrant variant Lys3326X in BRCA2 only in breast cancer cases.

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Specific Aspects of Consanguinity: Some Examples from the Tunisian Population

Cited by 18 publications

References 38 publications

H syndrome: Clinical, histological and genetic investigation in Tunisian patients

H syndrome: Clinical, histological and genetic investigation in Tunisian patients

Clinical and Genetic Heterogeneity in Six Tunisian Families With Horizontal Gaze Palsy With Progressive Scoliosis: A Retrospective Study of 13 Cases

Whole exome sequencing reveals a combination of rare high and low penetrance variants that correlates with familial breast cancer relative risk

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