Screening of the Eight BBS Genes in Tunisian Families: No Evidence of Triallelism

Smaoui, Nizar; Chaâbouni, M; Sergeev, Yuri V.; Kallel, Habib; Li, Shouling; Mahfoudh, Neila; Mâazoul, Faouzi; Kammoun, H.; Gandoura, Najoua; Bouaziz, Asma; Nouiri, Ezzedine; Mrad, Ridha; Chaâbouni, Habiba; Hejtmancik, J. Fielding

doi:10.1167/iovs.05-1334

Cited by 56 publications

(55 citation statements)

References 40 publications

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“…In addition to the most "classic" features of BBS our patients showed early onset of elevated triglyceride and cholesterol. Our mutational analysis observations are in agreement with previously published data suggesting that BBS7 and TTC8 are infrequently mutated in the overall BBS population (Hichri, et al, 2005;Katsanis, 2004;Smaoui, et al, 2006), that there is enrichment for null mutations and that these are seen across different ancestral backgrounds.…”

Section: Discussionsupporting

confidence: 92%

“…Our patients with BBS7 mutations did not show distinguishing systemic features when compared to the patients described in previous reports. (Azari, et al, 2006;Hichri, et al, 2005;Katsanis, 2004;Smaoui, et al, 2006). All patients were obese, had digit abnormalities, and displayed some degree of cognitive impairment and developmental delay.…”

Section: Phenotype Assessmentsmentioning

confidence: 99%

“…BBS1 and BBS10 are major contributors to the disease, each accounting for at least 20% of the mutational load. The remaining BBS genes are mutated in 5% or less of cases Badano, et al, 2003a;Hichri, et al, 2005;Smaoui, et al, 2006;Stoetzel, et al, 2006;Stoetzel, et al, 2007). The recognition that BBS is a ciliopathy is improving our understanding of the role of the BBS genes (Badano et al, 2006b), as well as the basis of some observed defects, underscoring the critical role of primary cilia in numerous disease processes.…”

Section: Introductionmentioning

confidence: 99%

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BBS7andTTC8(BBS8) mutations play a minor role in the mutational load of Bardet-Biedl syndrome in a multiethnic population

et al. 2009

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Bardet Biedl syndrome is a genetically heterogeneous ciliopathy with fourteen genes currently identified. To date, mutations in BBS7 and TTC8 (BBS8) were reported in 4.2% and 2.8% of BBS families respectively. We sequenced the coding regions of BBS7 and TTC8 in 35 BBS families of diverse ancestral backgrounds. In addition, the role of putative modifier genes on phenotype severity; NXNL1 and MGC1203 c.430C>T, was assessed. Genotype-phenotype correlation was explored in patients with identified mutations. Four novel pathogenic BBS7 changes were identified in 2/35 families (5.7%). In one family with two affected individuals with BBS7 mutations, a more severe phenotype was observed in association with a third mutation in BBS4. The overall retinal phenotype appeared more severe than that seen in patients with BBS1 mutations. This study confirms the small role of BBS7 and TTC8 in the overall mutational load of BBS patients. The variability of the ocular phenotype observed, could not be explained by the putative modifier genes; NXNL1 and MGC1203 c.430C>T.

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Section: Discussionsupporting

confidence: 92%

Section: Phenotype Assessmentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BBS7andTTC8(BBS8) mutations play a minor role in the mutational load of Bardet-Biedl syndrome in a multiethnic population

et al. 2009

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“…[19][20][21][22][23][24][25] Others, however, failed to demonstrate this oligogenic model and debate continues as to the magnitude of oligogenicity in the inheritance of BBS. 12,[26][27][28][29][30] It is important to highlight that oligogenicity here is used in the context of penetrance (the classic all-or-none definition); otherwise, there is little doubt that epistasis is a ubiquitous phenomenon in systems biology. Indeed, it has long been realized that there is no single disease that is 'monogenic' in the strict sense of the word.…”

Section: Introductionmentioning

confidence: 99%

In search of triallelism in Bardet–Biedl syndrome

et al. 2012

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Bardet-Biedl syndrome (BBS) is a model disease for ciliopathy in humans. The remarkable genetic heterogeneity that characterizes this disease is consistent with accumulating data on the interaction between the proteins encoded by the 14 BBS genes identified to date. Previous reports suggested that such interaction may also extend to instances of oligogenic inheritance in the form of triallelism which defies the long held view of BBS as an autosomal recessive disease. In order to investigate the magnitude of triallelism in BBS, we conducted a comprehensive analysis of all 14 BBS genes as well as the CCDC28B-modifier gene in a cohort of 29 BBS families, most of which are multiplex. Two in trans mutations in a BBS gene were identified in each of these families for a total of 20 mutations including 12 that are novel. In no instance did we observe two mutations in unaffected members of a given family, or observe the presence of a third allele that convincingly acted as a modifier of penetrance and supported the triallelic model of BBS. In addition to presenting a comprehensive genotype/phenotype overview of a large set of BBS mutations, including the occurrence of nonsyndromic retinitis pigmentosa in a family with a novel BBS9 mutation, our study argues in favor of straightforward autosomal recessive BBS in most cases.

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“…a third allele, which they speculate is necessary and perhaps sufficient for expression of any symptoms of the disease [87][88][89]. However, this model has been challenged by others [90][91][92][93][94], and at least one group maintains that all individuals that they have studied with two autosomal recessive mutations have 100% 'penetrance', but with variable expression, i.e. one individual might only have retinitis pigmentosa whereas another individual might have the full-blown symptoms of BardetBiedl syndrome [90].…”

Section: "Those Who Have Given Any Attention To Congenital Mental Lesmentioning

confidence: 99%

Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

Lyon

O'Rawe

2015

The Genetics of Neurodevelopmental Disorders

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Screening of the Eight BBS Genes in Tunisian Families: No Evidence of Triallelism

Abstract: All families in which mutations were identified show changes in both copies of the mutant gene, and inheritance patterns in all families are consistent with autosomal recessive inheritance excluding any evidence of triallelism in the BBS genes in Tunisia.

Cited by 56 publications

References 40 publications

BBS7andTTC8(BBS8) mutations play a minor role in the mutational load of Bardet-Biedl syndrome in a multiethnic population

BBS7andTTC8(BBS8) mutations play a minor role in the mutational load of Bardet-Biedl syndrome in a multiethnic population

In search of triallelism in Bardet–Biedl syndrome

Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

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