Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome: Identification of nine novel mutations across BBS1, BBS2, BBS4, BBS7, BBS9, BBS10 genes

Solmaz, Aslı Ece; Önay, Hüseyin; Atik, Tahir; Aykut, Ayça; Gunes, Meltem Cerrah; Yüreğir, Özge Özalp; Baş, Veysel Nijat; Hazan, Fılız; Kırbıyık, Özgür; Özkınay, Ferda

doi:10.1016/j.ejmg.2015.10.011

Cited by 36 publications

(39 citation statements)

References 48 publications

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“…The literature search was performed according to the protocol preregistered in Prospero (CRD42018096099) and it followed the PRISMA guidelines whenever applicable (Table S1 and Figure S1). In total, we identified 85 relevant studies (Abu Safieh et al, ; Agha et al, ; Ajmal et al, ; Al‐Hamed et al, ; Alazami et al, ; Aldahmesh et al, ; Azari et al, ; Badano, ; Baker et al, ; Bee, Chawla, & Zhao, ; Bennouna‐Greene et al, ; Billingsley et al, ; Billingsley, Vincent, Deveault, & Heon, ; Branfield Day et al, ; Braun et al, ; Bujakowska et al, ; Castro‐Sanchez et al, ; Chaki et al, ; Chul Yoon et al, ; Cox et al, ; Davies, ; Deveault et al, ; Ece Solmaz et al, ; Esposito et al, ; Estrada‐Cuzcano, Koenekoop, et al, ; Estrada‐Cuzcano, Neveling, et al, ; Fan et al, ; Fattahi et al, ; Fedick et al, ; Frank et al, ; Gerth, Zawadzki, Werner, & Heon, ; Ghadami et al, ; González‐del Pozo et al, ; Harville et al, ; Heon et al, ; Hjortshoj, Gronskov, Brondum‐Nielsen, & Rosenberg, ; Hjortshoj et al, ; Hulleman et al, ; Iannaccone et al, ; Innes et al, ; Iurian, Arts, Brunner, & Fintina, ; Janssen et al, ; Kamme, Mayer, Strom, Andréasson, & Weisschuh, ; Katsanis et al, ; Katsanis et al, ; Kerr, Bhan, & Héon, ; A. O. Khan, Decker, Bachmann, Bolz, & Bergmann, ; S. Khan et al, , S. A. Khan et al, ; Laurier et al, ; Leitch et al, ; Lim et al, ; Lindstrand et al, ; Lindstrand et al, ; M'Hamdi et al, ; Maria et al,…”

Section: Resultsmentioning

confidence: 99%

Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

et al. 2019

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Bardet‐Biedl syndrome (BBS) is a recessive genetic disease causing multiple organ anomalies. Most patients carry mutations in genes encoding for the subunits of the BBSome, an octameric ciliary transport complex, or accessory proteins involved in the BBSome assembly or function. BBS proteins have been extensively studied using in vitro, cellular, and animal models. However, the molecular functions of particular BBS proteins and the etiology of the BBS symptoms are still largely elusive. In this study, we applied a meta‐analysis approach to study the genotype‐phenotype association in humans using our database of all reported BBS patients. The analysis revealed that the identity of the causative gene and the character of the mutation partially predict the clinical outcome of the disease. Besides their potential use for clinical prognosis, our analysis revealed functional differences of particular BBS genes in humans. Core BBSome subunits BBS2, BBS7, and BBS9 manifest as more critical for the function and development of kidneys than peripheral subunits BBS1, BBS4, and BBS8/TTC8, suggesting that incomplete BBSome retains residual function at least in the kidney.

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Section: Resultsmentioning

confidence: 99%

Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

et al. 2019

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“…Although oligogenic inheritance is described, it is a highly heterogeneous condition and to date 21 genes (BBS 1-19, NPHP1 and IFT172) that account for more than 80% of affected individuals have been implicated. [10] Most of the genes code for proteins belonging to two functional groups. BBS 1,2,4,5,7,8 and 9 are responsible for the formation of a complex known as the BBSome, important in promoting ciliogenesis.…”

Section: To Prof Peter Beighton 'Do Genetics and See The World ' …mentioning

confidence: 99%

“…A stratified approach of testing in BBS, prioritising mutations and genes with greatest frequency, has been suggested, [15] although next generation sequencing panels may be a better strategy in more heterogeneous populations. [10] In a resource-constrained SA setting with limited access to multigene panels, first-line testing for the K243IfsX15 mutation in black South Africans with features of BBS is recommended and can be expected to provide a high diagnostic yield. Families with a positive genetic diagnosis can then be offered the option of prenatal diagnosis and carrier testing of the at-risk relatives.…”

Section: The New Millenniummentioning

confidence: 99%

Bardet Biedl syndrome in South Africa: A single founder mutation

et al. 2016

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Background. Bardet Biedl syndrome (BBS) is a multisystem disorder characterised by obesity, polydactyly, intellectual disability and loss of vision due to a progressive retinopathy. Although typically a highly heterogeneous autosomal recessive disease, homozygosity for single mutation in BBS 10 has been identified in a significant number of affected individuals tested in South Africa (SA). Objectives. To delineate the ethnic distribution and clinical phenotype in a cohort of SA BBS patients with the K243IfsX15 mutation in BBS 10 and discuss the implications for genetic testing of and counselling for this disorder in SA.Method. This was a descriptive cross-sectional study collating clinical and laboratory data retrospectively in a genetically homogenous subgroup of BBS patients from SA. Results. A total of 76 patients from 74 families were tested. Homozygosity for the K243IfsX15 BBS 10 mutation was found in 50 families (67%) and heterozygosity for the same mutation in an additional two affected individuals. With the exception of one patient of mixed ancestry, all were black South Africans from different language groups. This is in keeping with the observation that BBS is more common in this ethnic group compared with white and coloured patients in SA, first made by Prof. Beighton nearly 3 decades ago. A subset of 15 patients available for detailed phenotyping confirmed consistency with well-described features of the disorder, with some overlap with other ciliopathies. The onset of visual impairment was early in our cohort, before the age of 8 years, cognitive impairment was significant, and renal and cardiac abnormalities were infrequently encountered. Conclusion. The high frequency of homozygosity for a single mutation in an ethnic subset of the SA population is strongly suggestive of a founder effect. This has allowed establishment of a diagnostic test with a high yield in our local population. Better understanding of the phenotype will improve earlier recognition of the disorder to allow for appropriate intervention. Testing can confirm but not negate a clinical diagnosis, and can permit carrier and prenatal testing in informative families.

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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.…”

mentioning

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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Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome: Identification of nine novel mutations across BBS1, BBS2, BBS4, BBS7, BBS9, BBS10 genes

Cited by 36 publications

References 48 publications

Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

Bardet Biedl syndrome in South Africa: A single founder mutation

Bardet-Biedl Syndrome

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