Comprehensive Molecular Diagnosis of Bardet-Biedl Syndrome by High-Throughput Targeted Exome Sequencing

Xing, Dongjun; Zhang, Hongxing; Huang, Na; Wu, Kun; Huang, Xiu‐Feng; Huang, Fang; Tong, Yi; Pang, Chi‐Pui; Qu, Jia; Jin, Zi‐Bing

doi:10.1371/journal.pone.0090599

Cited by 41 publications

(28 citation statements)

References 26 publications

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“…Of note, among the total 124 mutation described in this study, 79 mutations were previously reported worldwide. We previously screened five patients with Bardet-Biedl syndrome for BBS genes 10 and five patients with Usher syndrome for USH genes 7 using the same panel; these were considered pilot studies to test the methodology and have been excluded from this study. Summarizing all these results, the detection rate was 57.7% (109/189).…”

Section: Discussionmentioning

confidence: 99%

“…9 In pilot studies, we successfully performed molecular diagnoses in patients with Usher syndrome and Bardet-Biedl syndrome by assessing a panel of 144 known genes. 7,10 Despite success in previous studies, there is still a large proportion of patients with IRD who have unidentified genetic mutations. 2 In addition, there are few thorough studies of the relationship between specific genotypes and phenotypes.…”

Section: Introductionmentioning

confidence: 99%

“…9,10 Many novel or unrecognized genes interact with known targets of IRD. 12,13 In addition, variations in microRNA (miRNA) expression could lead to a significant abnormality in the retina.…”

Section: Introductionmentioning

confidence: 99%

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Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Huang

et al. 2015

Genetics in Medicine

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181

126

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Purpose: Inherited retinal dystrophy (IRD) is a leading cause of blindness worldwide. Because of extreme genetic heterogeneity, the etiology and genotypic spectrum of IRD have not been clearly defined, and there is limited information on genotype-phenotype correlations. The purpose of this study was to elucidate the mutational spectrum and genotype-phenotype correlations of IRD. Methods:We developed a targeted panel of 164 known retinal disease genes, 88 candidate genes, and 32 retina-abundant microRNAs, used for exome sequencing. A total of 179 Chinese families with IRD were recruited. Results:In 99 unrelated patients, a total of 124 mutations in known retinal disease genes were identified, including 79 novel mutations (detection rate, 55.3%). Moreover, novel genotype-phenotype correlations were discovered, and phenotypic trends noted. Three cases are reported, including the identification of AHI1 as a novel candidate gene for nonsyndromic retinitis pigmentosa. Conclusion:This study revealed novel genotype-phenotype correlations, including a novel candidate gene, and identified 124 genetic defects within a cohort with IRD . The identification of novel genotype-phenotype correlations and the spectrum of mutations greatly enhance the current knowledge of IRD phenotypic and genotypic heterogeneity, which will assist both clinical diagnoses and personalized treatments of IRD patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Huang

et al. 2015

Genetics in Medicine

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181

126

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“…Up to now, only a few instances of BBS have been reported in Eastern Europe, Asia, South America, and Africa, and systematic BBS studies still remain to be done in these regions Xing et al, 2014;Ece Solmaz et al, 2015;Hirano et al, 2015;Suspitsin et al, 2015]. There are (1) the Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS) at the Marshfield Clinic (https://www.marshfieldclinic.org/services/bardet-biedl-syndrome-(bbs); https://cribbs.marshfieldclinic.org/), (2) the Europeanbased EURO-WABB registry [Farmer et al, 2013], and a number of robust international studies Ajmal et al, 2013;Fattahi et al, 2014] attempting to attract unstudied patients to BBS research.…”

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confidence: 99%

Bardet-Biedl Syndrome

Suspitsin

Imyanitov²

2016

Mol Syndromol

111

122

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Bardet-Biedl syndrome (BBS) is a rare autosomal recessive genetic disorder. It is characterized by heterogeneous clinical manifestations including primary features of the disease (rod-cone dystrophy, polydactyly, obesity, genital abnormalities, renal defects, and learning difficulties) and secondary BBS characteristics (developmental delay, speech deficit, brachydactyly or syndactyly, dental defects, ataxia or poor coordination, olfactory deficit, diabetes mellitus, congenital heart disease, etc.); most of these symptoms may not be present at birth but appear and progressively worsen during the first and second decades of life. At least 20 BBS genes have already been identified, and all of them are involved in primary cilia functioning. Genetic diagnosis of BBS is complicated due to lack of gene-specific disease symptoms; however, it is gradually becoming more accessible with the invention of multigene sequencing technologies. Clinical management of BBS is largely limited to a symptomatic treatment. Mouse experiments demonstrate that the most debilitating complication of BBS, blindness, can be rescued by topical gene therapy. There is a published case report describing the delay of BBS symptoms by nutritional compensation of the disease-related biochemical deficiencies. Progress in DNA testing technologies is likely to rapidly resolve all limitations in BBS diagnosis; however, much slower improvement is expected with regard to BBS treatment.

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“…Next, the release of IFT27 allows the activation of BBS3/ARL6 by GTP binding and attachment of (20) Joubert Syndrome 8 612291 ARL13B Yes (21) Meckel Syndrome 9 614209 B9D1 No (22) Bardet-Biedl Syndrome 1 209900 BBS1 Yes (15,(23)(24)(25) Bardet-Biedl Syndrome 2 615981 BBS2 Yes (23,25,26) Bardet-Biedl Syndrome 3 600151 BBS3/ARL6 Yes (27) Bardet-Biedl Syndrome 4 600374 BBS4 Yes (23,25,28) Bardet-Biedl Syndrome 5 615983 BBS5 Yes (23,29) Bardet-Biedl Syndrome 6 605231 BBS6/MKKS Yes (25,30) Bardet-Biedl Syndrome 7 615984 BBS7 Yes (23) Bardet-Biedl Syndrome 8 608132 BBS8/TTC8 Yes (23)(24)(25) Bardet-Biedl Syndrome 9 615986 BBS9/PTHB1 Yes (31) Bardet-Biedl Syndrome 10 615987 BBS10 Yes (15,23,25,32) Bardet-Biedl Syndrome 11 615988 BBS11/TRIM32 No (33) Limb-girdle muscular dystrophy 2H 254110 Id. No (34) Bardet-Biedl Syndrome 12 615989 BBS12 Yes (23) Bardet-Biedl Syndrome 13 615990 BBS13/MKS1 Yes (15,35) Meckel Syndrome 1 249000 Id. No (36) Bardet-Biedl Syndrome 14 615991 BBS14/CEP290/NPHP6 Yes (15) Leber congenital amaurosis 611755 Id.…”

Section: Intraflagellar Transportmentioning

confidence: 99%

The cilium: a cellular antenna with an influence on obesity risk

et al. 2016

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Primary cilia are organelles that are present on many different cell types, either transiently or permanently. They play a crucial role in receiving signals from the environment and passing these signals to other parts of the cell. In that way, they are involved in diverse processes such as adipocyte differentiation and olfactory sensation. Mutations in genes coding for ciliary proteins often have pleiotropic effects and lead to clinical conditions, ciliopathies, with multiple symptoms. In this study, we reviewed observations from ciliopathies with obesity as one of the symptoms. It shows that variation in cilia-related genes is itself not a major cause of obesity in the population but may be a part of the multifactorial aetiology of this complex condition. Both common polymorphisms and rare deleterious variants may contribute to the obesity risk. Genotype-phenotype relationships have been noticed. Among the ciliary genes, obesity differs with regard to severity and age of onset, which may relate to the influence of each gene on the balance between pro-and anti-adipogenic processes. Analysis of the function and location of the proteins encoded by these ciliary genes suggests that obesity is more linked to activities at the basal area of the cilium, including initiation of the intraflagellar transport, but less to the intraflagellar transport itself. Regarding the role of cilia, three possible mechanistic processes underlying obesity are described: adipogenesis, neuronal food intake regulation and food odour perception.

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Comprehensive Molecular Diagnosis of Bardet-Biedl Syndrome by High-Throughput Targeted Exome Sequencing

Cited by 41 publications

References 26 publications

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Bardet-Biedl Syndrome

The cilium: a cellular antenna with an influence on obesity risk

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