Diagnosis Of Bardet-Biedl Syndrome Research Articles

Phenotypic diversity observed in a Chinese patient cohort with biallelic variants in Bardet-Biedl syndrome genes.

Bardet-Biedl syndrome (BBS) is a rare multisystem ciliopathy. The aim of this study was to describe the clinical and genetic features of a cohort of Chinese patients carrying biallelic BBS gene variants. We recruited 34 patients from 31 unrelated pedigrees who carried biallelic pathogenic variants in BBS genes. All patients underwent ophthalmic and systematic evaluations, as well as comprehensive molecular genetic analyses. Ultimately, 14 patients were followed up over time. We identified 47 diseasing-causing variants in 10 BBS genes; 33 were novel. Diagnosis of BBS and non-syndromic retinitis pigmentosa (RP) were established in 28 patients from 27 pedigrees and 6 patients, respectively. The two most prevalent genes in patients with BBS were BBS2 and BBS4, accounting for 51.8% of the probands. The patients exhibited clinical heterogeneity, from patients with all six primary clinical components to patients suffering from non-syndromic RP. The common components were retinal dystrophy, polydactyly, and obesity, with frequencies of 78.6% to 100%, while renal anomaly frequencies were only 7.1%. Patients exhibited early and severe visual defects and retinal degeneration. Patients with biallelic missense variants in BBS2 suffered fewer clinical symptoms and mild visual impairment. Patients with BBS10 variants tended to have cone dystrophy. Our study defined the mutated gene profiles and established the configuration of the variation frequencies for each BBS gene in Chinese patients. Overall, our patients showed early and severe visual defects and retinal degeneration. Genetic analysis is therefore crucial for diagnosis, genetic counseling, and future gene therapy in these patients.

Commentary: Retinitis pigmentosa in Laurence-Moon-Bardet-Biedl syndrome: Genomic sequencing, gene therapy, and gene editing.

Being a rare inherited retinal dystrophy, retinitis pigmentosa (RP) in Laurence–Moon–Bardet–Biedl syndrome (LMBBS) is typically described in case series and reports. In the current study,[1] the authors describe a detailed big data analysis of patients with RP which helps document the degree and progeression of vision loss in affected patients. It also helps depict in detail, associated systemic and ocular co-morbidities. Genetic testing in such patients helps significantly. The advantages are threefold. First, we are able to share the likely course and progression of vision loss to patients by comparing them with people reported to have similar mutations. Second, the inheritance pattern can be informed and discussed with patients, which helps in family planning. Last but not the least, knowing the mutation helps us discuss potential ongoing gene therapy clinical trials and therapies in development, if available, for the same mutation. That said, in a busy retina practice, often explaining the advantages of the same and discussing the nuances around it may not always be possible. Further, the genomic sequencing technology is financially formidable for most patients, restricting its applicability at present. LMBBS is caused by mutations in the BBS gene (BBS1–BBS21), which account for 80% of cases with a clinical diagnosis of Bardet Biedl Syndrome (BBS).[2] The BBS1 gene, which is the most commonly affected, is responsible for cilia formation in photoreceptors. The impact of BBS gene mutations is seen in ciliated cells. Therefore, photoreceptor changes accompany hearing loss and renal, gonadal, and intellectual dysfunction. Advances in gene therapy have received US Food and Drug Administration (FDA) approval for retinal dystrophy caused by RPE65 gene mutations (voretigene neparvovec), and clinical trials are in progress for various other mutations causing RP. However, targeting the BBS gene mutations via gene therapy has been found to be complex due to the structural stoichiometry of the BBSome protein.[3] Gene editing using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) received the Nobel Prize in 2020. This promising new technique allows for editing the mutation. The CRISPR effector molecules consist of a guide RNA and Cas9 protein. The guide RNA identifies the target DNA to be edited, and the Cas9 protein cleaves the DNA, following which DNA repair mechanisms take place, which can insert the desired DNA bases, thereby correcting the mutation.[4] The technique can, however, cause DNA editing at other areas of the genome, called off-target effects. To mitigate this, CRISPR base editing and prime editing have been developed.[5] The technology holds promise and is currently in clinical trials for mutations in the CEP290 gene causing RP, the Brilliance Trial.[6] The role of CRISPR is yet to be explored in BBS gene mutations and perhaps could form a prudent area to explore in the future. To conclude, LMBBS is an important syndrome affecting multiple organs and tissues, the retina being one of them. Such descriptive studies driven by big data analytics help elucidate clinical characteristics of rare inherited retinal dystrophies. In future, an associated relevant genetic analysis of the causative mutations will help describe the mutational landscape in our country and plan therapies for the same.

Clinical diagnosis of Bardet-Biedl syndrome: A case report

Clinical diagnosis of Bardet-Biedl syndrome: A case report

Novel sequence variants in the MKKS gene cause Bardet-Biedl syndrome with intra- and inter-familial variable phenotypes.

Bardet-Biedl syndrome (BBS) is a multisystem disorder involving retina, kidney, limbs, and nervous system. Additional features associated with BBS include dental anomalies, cardiovascular defects, hearing loss, and speech impairment (Beales et al. 1999; Ullah et al. 2017). Diagnosis of BBS is based on the presence of four out of six primary or three primary and two secondary phenotypes. Variation in the phenotypes within and among different families has been reported (Beales et al. 1999; Khan et al. 2016). So far, mutations have been reported in 21 disease-causing genes (BBS1–21) (Heon et al. 2016; Suspitsin and Imyanitov, 2016). BBS segregates in autosomal recessive manner. In rare cases, triallelic nature of BBS involving three mutated alleles in two genes has been reported as well. Genes causing BBS phenotypes play important roles in ciliogenesis. Defects in the formation or function of cilia result in syndromic form of BBS. Cilia are cell surface structures involved in cell locomotion, signaling, and chemo/mechano/photo-sensation. Due to localization of cilia in different organs including kidney, liver, pancreas, odontoblasts, retinal photoreceptors, and hypothalamic neurons, ciliary defects cause multisystem disorders. Three BBS proteins including BB6/MKKS, BBS10, and BBS12 form chaperonin complex required for BBsome formation. BBsome is composed of eight BBS proteins including BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, and BBIP10/BBS18. Chaperonin binds to BBS7 and stabilizes it and then interacts with BBS2 and BBS9 to form core of BBsome. Other members bind to BBsome core in order of BBS1, BBS5, BBS8, BBS4, and BBIP10 (Loktev et al. 2008). BBsome participates in the cilia formation. The present study was conducted with the permission of institutional review board of Qauid-i-Azam University Islamabad, Pakistan. Clinical features of affected individuals are presented in Figure 1. Affected members in the two families (A and B) showed previously reported primary features of BBS, which included polydactyly, learning difficulties, retinitis pigmentosa, truncal obesity, and hypogonadism (Khan et al. 2016). In addition, a male affected member of family A showed sparse hairs on scalp and face, and a rare secondary feature of dental anomalies. In the same family, one of the affected members (V-5) had polydactyly in both hands and feet, while the second affected member (V-6) showed this feature only in the right foot. Affected members of family B showed clinodactyly of toes as a secondary feature of BBS (Table S1, Supporting information). DNA from blood was extracted using Sigma GenElute Blood Genomic DNA kit (Sigma Aldrich, St Louis, MO, USA). Homozygosity mapping was performed by genotyping highly polymorphic microsatellite markers which were mapped previously in vicinity of the BBS genes (BBS1–21) ( Fig. S1). This was followed by Sanger sequencing using standard procedure (Ullah et al. 2015), which revealed two novel variants including c.775-775delA in family A and c.287C>T in family B in the MKKS. Mutation effect prediction tools (MutationTaster, SIFT, and Polyphen2) predicted the two novel variants to be deleterious and disease-causing (Table S2). Previously, the MKKS was mapped on chromosome 20p12.2. The gene encodes 570-amino acid long BBS6 protein. It contains three domains including equatorial, intermediate, and apical. The equatorial domain is connected to apical domain by intermediate domain through flexible hinges. The variant (p.Thr259Leufs*21) in MKKS/BBS6, found in family A, is located in the apical domain which is involved in substrate binding. The other variant (p.Ala96Val), found in family B, is located in the most conserved equatorial domain and is highly likely to disrupt its ATPase activity. The BBS6 is a member of chaperonin family, which is involved in the formation of BBsome complex. It is highly likely that sequence variants in the BBS6 would disrupt formation of such a complex leading to buckle cilia formation. We have observed variation in the phenotypes not only in the two families, but also among patients of the same family (Table S1). Position and nature of mutation alter the structure and function of protein differentially. Genetic background and extent of change in the structure and function of protein might be responsible for the intra- and inter-familial variability of phenotypes. In conclusion, we have identified two novel sequence variants in the BBS6 causing BBS phenotypes in two different consanguineous families. This study not only supports the previously reported findings of intra- and inter-familial variations in features of BBS families, but also further extend spectrum of the mutations in the MKKS gene. This study will support genetic testing of BBS patients in Pakistan. We are highly thankful to the family members for their participation in the present research project. MU was supported by Higher Education Commission Islamabad, Pakistan Indigenous PhD fellowship. The authors declare that they have no competing interests. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Spot Diagnosis of a Daedalian Genetic Disorder: Bardet-Biedl Syndrome.

A 15-year-old boy with night blindness since the age of six presented to the outpatient wing with a history of growth retardation, poor scholastic performance and failure to attain secondary sexual characters. Retinal imaging showed the presence of pigmentary retinal degeneration and attenuated vessels suggesting retinitis pigmentosa [Table/Fig-1]. Physical examination revealed dysmorphic facies [Table/Fig-2] - widened intercanthal distance, low set ears, depressed nasal bridge and a flattened occiput [Table/Fig-3]. Also truncal obesity [Table/Fig-3], shortened metacarpals/phalanges [Table/Fig-4], polydactyly [Table/Fig-5], and underdeveloped testes were noted. In view of the constellation of findings, a diagnosis of Bardet–Biedl Syndrome (BBS) was made. Nutritional supplementation was advised and the patient was referred for IQ assessment and genetic counseling. [Table/Fig-1]: Fundus photograph of the left eye demonstrating pigmentary changes and arteriolar attenuation characteristic of retinitis pigmentosa. [Table/Fig-2]: Dysmorphic face with depressed nasal bridge, widened intercanthal distance and low set ears. [Table/Fig-3]: Depicting the flattened occiput and trucal obesity. [Table/Fig-4]: Brachydactyly, shortened metacarpals and phalanges. [Table/Fig-5]: Postaxial polydactyly. In 1866, Laurence and Moon described four patients with retinal degeneration, obesity, and cognitive deficit [1]. Bardet and Biedl separately reported similarly affected individuals who also had postaxial polydactyly and the condition was coined Laurence– Moon–Bardet–Biedl syndrome [2,3]. The syndrome is often divided into two entities: Laurence–Moon syndrome and Bardet–Biedl Syndrome (BBS), but since there is considerable overlap, BBS is now the globally accepted name. Beales et al., proposed a modified criteria in 1999, requiring four primary features or three primary features with two secondary features for the diagnosis [4]. Rod-cone dystrophy, polydactyly, truncal obesity, genital anomalies, chronic kidney disease and learning disabilities form the primary features, while speech delay, developmental delay, diabetes, dental anomalies, congenital heart disease, brachydactyly/syndactyly, ataxia/poor coordination and anosmia/hyposmia are the secondary features. The diagnosis of BBS is delayed and considered only when the child develops visual problems associated with rod-cone dystrophy [5]. Postaxial polydactyly may be the only hint to the diagnosis at birth and hence its presence should alert physicians to look for other features of BBS [5]. Our patient had five primary and three secondary features. BBS is a rare and complex syndrome, autosomal recessively inherited, involving mutations of proteins that form components of the ciliary apparatus. But as emphasized by our patient, the diagnosis remains clinical. Treatment and rehabilitation involve a multidisciplinary approach. Early recognition and treatment of co-morbidities are imperative to improve the quality of life.

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

Bardet-Biedl Syndrome (BBS) is a rare, autosomal-recessive ciliopathy characterized by obesity, rod-cone dystrophy, postaxial polydactyly, renal abnormalities, genital abnormalities and learning difficulties. To date, mutations in 21 different genes have been described as being responsible for BBS. Recently sequential gene sequencing has been replaced by next generation sequencing (NGS) applications. In this study, 15 patients with clinically diagnosed BBS were investigated using a next generation sequencing panel which included 17 known BBS causing genes (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, NPHP6, WDPCP, SDCCAG8, NPHP1).A genetic diagnosis was achieved in 13 patients (86.6%) and involved 9 novel and 3 previously described pathogenic variants in 6 of 17 BBS causing genes. BBS10 and BBS1 were the most commonly involved genes with frequencies of 31% and 23% respectively. Three of the 13 patients had an affected sibling. All affected siblings were found to be homozygous for the mutation detected in the proband. No evidence of triallelic inheritance was detected.Although limited association between certain genes and phenotypic features has been observed in this study, it is considered that additional studies are needed to better characterize the genotype–phenotype correlation of BBS. Our results demonstrate that NGS panels are feasible and effective method for providing high diagnostic yields in the diseases caused by multiple genes such as BBS.

Renal Dysplasia in Bardet-Biedl Syndrome/ Бубрежна Дисплазија Кај Бардет Бидл Синдром

Bardet-Biedl syndrome (BBS) is a multisystem genetic disorder characterized with central obesity, pigmentary retinopathy, polydactyly, mental retardation, and hypogenitalism. Renal abnormalities have been recognized as a cardinal feature of the disease with serious prognostic implication. The aim of this study was to analyze the renal status in children with BBS and to implement appropriate interventions in those with progressive course Patients and methods: The diagnosis of BBS was established on the basis of criteria proposed by Beales et al. (J Med Genet 1999). Imaging of the kidneys and urinary tract was performed with ultrasound study, Tc99(m)DMSA scan and a cystographic study. Twenty four hour urine collections were obtained for estimation of proteinuria and creatinine clearance. Blood pressure was monitored at clinical visits or as 24-hour ambulatory monitoring. There were 4 children (2 males, 2 females). All four children displayed abnormal kidney ultrasound and Tc99(m)DMSA scan resembling dysplastic kidney(s). Two of them had overt proteinuria (glomerulo-tubular pattern). Three children had normal blood pressure and glomerular filtration rate (GFR): 107, 145 and 95 ml/min/1.73m(2), and the fourth had hypertension and progressive worsening of the GFR at 65 ml/min/1.73m(2). Children with BBS should undergo imaging studies of the kidneys and urinary tract at initial work up; in those with renal dysplasia proteinuria, GFR and blood pressure should be regularly monitored to slow down progression to terminal renal failure.

Syndromic obesity: clinical implications of a correct diagnosis

BackgroundAlthough individual occurrence is rare, syndromic obesity with mental retardation has been reported in conjunction with 140 different diseases.Case presentationThe patient was born at term after a pregnancy complicated by threatened miscarriage. A diagnosis of Bardet-Biedl syndrome (BBS; OMIM #209900) was made in another hospital when she was 8 years old, but other clinical problems emerged subsequently. She came to our attention for the first time when she was 14 years old. The clinical picture, characterized by the presence of ophtalmological, renal, endocrinological, and liver disorders associated with a peculiar weight growth pattern, was more suggestive for Alström syndrome (ALMS; OMIM #203800); consequently, a genetic study was performed. Genetic analysis revealed a novel compound heterozygous frameshift mutation on exon 8 of ALMS1 (c. [3251_3258delCTGACCAG] and c. [6731delA]), which has not previously been described.ConclusionEarly onset of retinal degeneration associated with obesity represents a diagnostic challenge in paediatric and genetic practice, although the absence of skeletal abnormalities and developmental delay could help in addressing the clinical diagnosis. Confirmation of clinical suspicion by genetic analysis has been diriment in this case, since only a single gene is known to cause ALMS.

Diagnosis of Bardet-Biedl Syndrome in Consecutive Pregnancies Affected with Echogenic Kidneys and Polydactyly in a Consanguineous Couple

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathic human genetic disorder with variable expression that is difficult to diagnose in pregnancy without known risk factors. Homozygosity testing has been shown to be a useful tool in identifying BBS mutations and candidate genes in affected individuals. We present the first case of prenatal diagnosis of BBS in consecutive pregnancies aided by homozygosity testing via SNP microarray analysis. This case demonstrates a novel approach to the evaluation of recurrent echogenic kidneys in consanguineous couple with no significant family history.

Mutational Analysis of SDCCAG8 in Bardet-Biedl Syndrome Patients with Renal Involvement and Absent Polydactyly

Purpose: To assess for SDCCAG8 mutations in Bardet-Biedl syndrome (BBS) subjects with renal involvement and no polydactyly, and to describe phenotypic characteristics of SDCCAG8-related disease.Material and Methods: Five patients (from 4 pedigrees) with clinical diagnosis of BBS, who had retinal and renal involvement and no polydactyly, were assessed. Sequence analysis of SDCCAG8 was undertaken and a detailed clinical review of an affected sibship was performed.Results: A sibship of East Indian origin who carried a putative clinical diagnosis of BBS had compound heterozygous mutations in SDCCAG8 (p.Thr482LysfsX12/p.Asp543AlafsX24). The renal involvement was early and required transplant in both cases. Both were short statured and had asthma since childhood. The younger sister also had non-alcoholic fatty liver disease. Visual acuity and central fields were preserved in the teenage years in both patients. The optical coherence tomography showed preservation of the retinal lamination at the fovea; fundus autofluorescence demonstrated a perifoveal ring of hyperfluorescence as commonly observed in other forms of retinitis pigmentosa. Full-field electroretinogram revealed rod function to be more severely affected than cone function in both cases.Conclusion: Our results and prior literature suggest that SDCCAG8 could play an important role in presumed BBS patients affected with severe kidney disease and absent polydactyly. This report enhances the phenotypic description of SDCCAG8-related disease.

Bardet-Biedl Syndrome: An Atypical Phenotype in Brothers with a Proven BBS1 Mutation

Background: To report the clinical findings in two brothers presenting with a pigmentary retinopathy and post-axial polydactyly, who were found to have a mutation in the BBS1 gene, confirming a diagnosis of Bardet-Biedl syndrome (BBS). Materials and Methods: Documentation of the clinical history, electrophysiological investigations, clinical examination and ocular findings of two brothers born to non-consanguineous white parents, with careful delineation of their clinical phenotypes. Screening of the BBS 1 gene on chromosome 11q13 by PCR-amplified exon alterations followed by direct sequencing was carried out to identify pathogenic mutations. Results: Although both probands had polydactyly and the characteristic ocular signs of BBS on both ophthalmological examination and electro-retinography, neither of them had dysmorphic facial features, obesity, hypogonadism, cognitive impairment, or renal anomalies. The first proband did have mild learning difficulties, although this did not restrict him in activities of daily living. Both probands were homozygous positive for the presence of a c.1169T > G (p.Met390Arg) mutation in BBS1. Conclusion: Although neither proband fulfilled the typical criteria for BBS, this diagnosis was confirmed on mutation analysis. These cases serve to highlight the degree of clinical variability observed in BBS which may be under-diagnosed in patients with milder phenotypes.

Treatment of Gingival Overgrowth in a Child With Bardet‐Biedl Syndrome

Bardet-Biedl syndrome (BBS) is a rare, heterogeneous, autosomal recessive condition, primarily characterized by polydactyly, obesity, mental retardation, hypogonadism, retinopathy, and renal failure. Dental anomalies, regarded as secondary manifestations, include hypodontia, microdontia, short roots, and deep palate. Few reports in the literature have described the oral manifestations of BBS. This article reports a case of BBS in a boy who presented some typical oral manifestations added to a generalized gingival overgrowth, an anomaly that had not been reported previously in patients with this syndrome. A 12-year-old white male presented with a diagnosis of BBS and chief complaint of gingival enlargement in the anterior segment of both arcades. The treatment plan included surgical removal of the overgrown gingiva followed by orthodontic therapy. The excised tissues were submitted to histologic analysis. There was no sign of recurrence 1 year after gingivectomy. Histopathology revealed a dense connective tissue with a mild inflammatory infiltrate, irregularly arranged fiber bundles, and epithelial acanthosis, which is characteristic of gingival overgrowth. The gingival overgrowth was treated successfully by gingivectomy. The periodontal surgery minimized the functional, social, and emotional consequences of the oral manifestation associated with the syndrome.

Hydrometrocolpos and polydactyly: a common neonatal presentation of Bardet-Biedl and McKusick-Kaufman syndromes

McKusick-Kaufman syndrome (MKKS) is a rare, recessively inherited syndrome reported mainly in young children and is characterised by vaginal atresia with hydrometrocolpos, postaxial polydactyly, and congenital heart defect. Bardet-Biedl syndrome...