Ophthalmic and Genetic Features of Bardet Biedl Syndrome in a German Cohort

Nasser, Fadi; Kohl, Susanne; Kurtenbach, Anne; Kempf, Melanie; Biskup, Saskia; Zuleger, Theresia; Haack, Tobias B.; Weisschuh, Nicole; Štingl, Katarína; Zrenner, Eberhart

doi:10.3390/genes13071218

Cited by 6 publications

(8 citation statements)

References 92 publications

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“…We observed BBS10 as the most frequently mutated gene ( N = 16) and p.C91Lfs*95 was seen in three probands (Table 2). BBS1, BBS2, ARL6, BBS5, MKKS, BBS7 , and BBS12 genes were seen in >5% of our study cohort which is comparable with the world wide reports except for BBS1 and BBS12 genes 26–28 . Variations in BBS1 gene were frequently reported worldwide (23%), 2 while only 7.4% of our patients harbored the same and the widely reported missense variant p.M390R was not seen in our probands.…”

Section: Discussionsupporting

confidence: 88%

“…BBS1, BBS2, ARL6, BBS5, MKKS, BBS7, and BBS12 genes were seen in >5% of our study cohort which is comparable with the world wide reports except for BBS1 and BBS12 genes. [26][27][28] African regions 23 while we observed BBS4 variations in 2.7% and BBS5 variations in 4.6% of our patients. Frequency of MKKS and BBS7 variations were quite similar to the frequencies reported in other populations (MKKS-5.4%, 31 BBS7-1.5%-3%).…”

Section: Molecular Genetic Spectrum In Bbs Patientssupporting

confidence: 47%

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Mutation profile of Bardet‐Biedl syndrome patients from India: Implicative role of multiallelic rare variants and oligogenic inheritance pattern

Gnanasekaran,

Chandrasekhar,

Kandeeban

et al. 2023

Clinical Genetics

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Bardet‐Biedl syndrome (BBS), a rare primary form of ciliopathy, with heterogeneous clinical and genetic presentation is characterized by rod cone dystrophy, obesity, polydactyly, urogenital abnormalities, and cognitive impairment. Here, we delineate the genetic profile in a cohort of 108 BBS patients from India by targeted gene sequencing‐based approach for a panel of ciliopathy (including BBS) and other inherited retinal disease genes. We report here a higher frequency of BBS10 and BBS1 gene variations. A different spectrum of variations including a putatively novel gene TSPOAP1, for BBS was identified. Increased percentage frequency of digenic variants (36%) in the disease cohort, role of modifiers in familial cases are some of the salient observations in this work. This study appends the knowledge of BBS genetics pertaining to patients from India. We observed a different molecular epidemiology of BBS patients in this study cohort compared to other reports, which emphasizes the need for molecular testing in affected patients.

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Section: Discussionsupporting

confidence: 88%

Section: Molecular Genetic Spectrum In Bbs Patientssupporting

confidence: 47%

Mutation profile of Bardet‐Biedl syndrome patients from India: Implicative role of multiallelic rare variants and oligogenic inheritance pattern

Gnanasekaran,

Chandrasekhar,

Kandeeban

et al. 2023

Clinical Genetics

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“…Twelve clinical studies reported morphofunctional characteristics of the IRDs [ 8 , 14 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. Patients were divided into five groups according to their IRD.…”

Section: Morphofunctional Finding In Irdmentioning

confidence: 99%

“…The third study, by Fadi Nasser et al [ 52 ], was characterized by OCT and ERG, including a cohort of sixty-one German patients aged between 5 and 56 years with 51 different biallelic mutations. OCT images of all 20 patients with BBS10 showed atrophy of the photoreceptor layer and loss of photoreceptor cells, mostly together with wrinkles of the inner limiting membrane.…”

Section: Morphofunctional Finding In Irdmentioning

confidence: 99%

Gene Therapy in Hereditary Retinal Dystrophies: The Usefulness of Diagnostic Tools in Candidate Patient Selections

Malvasi,

Casillo,

Avogaro

et al. 2023

IJMS

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Purpose: Gene therapy actually seems to have promising results in the treatment of Leber Congenital Amaurosis and some different inherited retinal diseases (IRDs); the primary goal of this strategy is to change gene defects with a wild-type gene without defects in a DNA sequence to achieve partial recovery of the photoreceptor function and, consequently, partially restore lost retinal functions. This approach led to the introduction of a new drug (voretigene neparvovec-rzyl) for replacement of the RPE65 gene in patients affected by Leber Congenital Amaurosis (LCA); however, the treatment results are inconstant and with variable long-lasting effects due to a lack of correctly evaluating the anatomical and functional conditions of residual photoreceptors. These variabilities may also be related to host immunoreactive reactions towards the Adenovirus-associated vector. A broad spectrum of retinal dystrophies frequently generates doubt as to whether the disease or the patient is a good candidate for a successful gene treatment, because, very often, different diseases share similar genetic characteristics, causing an inconstant genotype/phenotype correlation between clinical characteristics also within the same family. For example, mutations on the RPE65 gene cause Leber Congenital Amaurosis (LCA) but also some forms of Retinitis Pigmentosa (RP), Bardet Biedl Syndrome (BBS), Congenital Stationary Night Blindness (CSNB) and Usher syndrome (USH), with a very wide spectrum of clinical manifestations. These confusing elements are due to the different pathways in which the product protein (retinoid isomer-hydrolase) is involved and, consequently, the overlapping metabolism in retinal function. Considering this point and the cost of the drug (over USD one hundred thousand), it would be mandatory to follow guidelines or algorithms to assess the best-fitting disease and candidate patients to maximize the output. Unfortunately, at the moment, there are no suggestions regarding who to treat with gene therapy. Moreover, gene therapy might be helpful in other forms of inherited retinal dystrophies, with more frequent incidence of the disease and better functional conditions (actually, gene therapy is proposed only for patients with poor vision, considering possible side effects due to the treatment procedures), in which this approach leads to better function and, hopefully, visual restoration. But, in this view, who might be a disease candidate or patient to undergo gene therapy, in relationship to the onset of clinical trials for several different forms of IRD? Further, what is the gold standard for tests able to correctly select the patient? Our work aims to evaluate clinical considerations on instrumental morphofunctional tests to assess candidate subjects for treatment and correlate them with clinical and genetic defect analysis that, often, is not correspondent. We try to define which parameters are an essential and indispensable part of the clinical rationale to select patients with IRDs for gene therapy. This review will describe a series of models used to characterize retinal morphology and function from tests, such as optical coherence tomography (OCT) and electrophysiological evaluation (ERG), and its evaluation as a primary outcome in clinical trials. A secondary aim is to propose an ancillary clinical classification of IRDs and their accessibility based on gene therapy’s current state of the art. Material and Methods: OCT, ERG, and visual field examinations were performed in different forms of IRDs, classified based on clinical and retinal conditions; compared to the gene defect classification, we utilized a diagnostic algorithm for the clinical classification based on morphofunctional information of the retina of patients, which could significantly improve diagnostic accuracy and, consequently, help the ophthalmologist to make a correct diagnosis to achieve optimal clinical results. These considerations are very helpful in selecting IRD patients who might respond to gene therapy with possible therapeutic success and filter out those in which treatment has a lower chance or no chance of positive results due to bad retinal conditions, avoiding time-consuming patient management with unsatisfactory results.

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“…To understand whether the clinical manifestations of BBS are consistent across patients worldwide, we compared the phenotypes of our Chinese cohort with those of the three cohorts from other countries: Spain, Germany, and India [16,17,18] (Table 2). The average age in the Chinese cohort was younger than that in the Spanish and German cohorts, while older than that in the Indian cohort.…”

Section: Phenotypic Comparison Between Our Chinese Cohort and Cohorts...mentioning

confidence: 99%

Molecular and Phenotypic Characteristics of Bardet-Biedl Syndrome in Chinese Patients

shiyang,

Zhang,

Ding

et al. 2023

Preprint

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Background Bardet-Biedl syndrome (BBS) is a type of non-motile ciliopathy. To date, 26 genes have been reported to be associated with BBS. However, BBS is genetically heterogeneous, with significant clinical overlap with other ciliopathies, which complicates diagnosis. Disability and mortality rates are high in BBS patients; therefore, it is urgent to improve our understanding of BBS. Thus, our study aimed to describe the genotypic and phenotypic spectra of BBS in China and to elucidate genotype-phenotype correlations. Methods Twenty Chinese patients diagnosed with BBS were enrolled in this study. We compared the phenotypes of Chinese BBS patients in this study with those from other countries to analyze the phenotypic differences across patients worldwide. In addition, genotype-phenotype correlations were described for our cohort. We also summarized all previously reported cases of BBS in Chinese patients (71 patients) and identified common and specific genetic variants in the Chinese population. Results Twenty-eight variants, of which 10 are novel, in 5 different BBS-associated genes were identified in 20 Chinese BBS patients.. By comparing the phenotypes of BBSome-coding genes (BBS2,7,9) with those of chaperonin-coding genes (BBS10,12), we found that patients with mutations in BBS10 and 12 had an earlier age of onset (1.10 Vs. 2.20, p < 0.01) and diagnosis (4.64 Vs. 13.17, p < 0.01), whereas patients with mutations in BBS2, 7, and 9 had a higher body mass index (28.35 Vs. 24.21, p < 0.05) and more vision problems (p < 0.05). Furthermore, in 91 Chinese BBS patients, mutations were predominant in BBS2 (28.89%) and BBS7 (15.56%), and the most frequent variants were in BBS2: c.534 + 1G > T (10/182 alleles) and BBS7: c.1002delT (7/182 alleles), marking a difference from the genotypic spectra of BBS reported abroad. Conclusions We recruited 20 Chinese patients with BBS for genetic and phenotypic analyses, and identified common clinical manifestations, pathogenic genes, and variants. We also described the phenotypic differences across patients worldwide and among different BBS-associated genes. This study involved the largest cohort of Chinese patients with BBS, and provides new insights into the distinctive clinical features of specific pathogenic variants.

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Ophthalmic and Genetic Features of Bardet Biedl Syndrome in a German Cohort

Cited by 6 publications

References 92 publications

Mutation profile of Bardet‐Biedl syndrome patients from India: Implicative role of multiallelic rare variants and oligogenic inheritance pattern

Mutation profile of Bardet‐Biedl syndrome patients from India: Implicative role of multiallelic rare variants and oligogenic inheritance pattern

Gene Therapy in Hereditary Retinal Dystrophies: The Usefulness of Diagnostic Tools in Candidate Patient Selections

Molecular and Phenotypic Characteristics of Bardet-Biedl Syndrome in Chinese Patients

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