The characterization and comorbidities of heterozygous Bardet-Biedl syndrome carriers.

Introduction: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with clinical features of retinal dystrophy, obesity, postaxial polydactyly, renal anomalies, learning disabilities, hypogonadism, and genitourinary abnormalities. Nevertheless, previous studies on the phenotypic traits of BBS heterozygous carriers have generated inconclusive results. The aim of our study was to investigate the impact of BBS heterozygosity on carriers when compared to non-carriers within the Taiwanese population. Materials and Methods: This study follows a hospital-based case-control design. We employed the Taiwan Biobank version 2 (TWBv2) array to identify three specific loci associated with BBS (rs773862084, rs567573386, and rs199910690). In total, 716 patients were included in the case group, and they were compared to a control group of 2,864 patients who lacked BBS alleles. The control group was selected through gender and age matching at a ratio of 1:4. The association between BBS-related loci and comorbidity was assessed using logistic regression models. Results: We found that BBS heterozygous carriers exhibited a significant association with elevated BMI levels, especially the variant rs199910690 in MKS1 (p=0.0037). The prevalence of comorbidities in the carriers' group was not higher than that in the non-carriers' group. Besides, the average values of the biochemistry data showed no significant differences, except for creatinine level. Furthermore, we conducted a BMI-based analysis to identify specific risk factors for chronic kidney disease (CKD). Our findings revealed that individuals carrying the CA/AA genotype of the BBS2 rs773862084 variant or the CT/TT genotype of the MKS1 rs199910690 variant showed a reduced risk of developing CKD, irrespective of their BMI levels. When stratified by BMI level, obese males with the MKS1 rs199910690 variant and obese females with the BBS2 rs773862084 variant exhibited a negative association with CKD development. Conclusion: We found that aside from the association with overweight and obesity, heterozygous BBS mutations did not appear to increase the predisposition of individuals to comorbidities and metabolic diseases. To gain a more comprehensive understanding of the genetic susceptibility associated with Bardet-Biedl Syndrome (BBS), further research is warranted.

Bardet-Biedl syndrome and related disorders in Japan.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by obesity, mental impairment, rod-cone dystrophy, polydactyly, male hypogonadism, and renal abnormalities. This disorder is caused by mutations in BBS1-21. Alström syndrome (AS), caused solely by mutations in ALMS1, is another genetic obesity syndrome clinically similar to BBS. We previously conducted the first nationwide survey of BBS in Japan and found four patients with genetically definite BBS. In this study, exome analyses were performed on new patients whose symptoms fulfilled the diagnostic criteria for BBS. We identified one reported heterozygous mutation in BBS1 (p.R429*) in one patient, two novel mutations (p.L493R and p.H719Y) in BBS20 in a second patient, and one novel mutation (p.Q920*) and one reported mutation (p.R2928*) in ALMS1 in a third patient, who was subsequently diagnosed with AS. The first patient with BBS was previously considered to have digenic heterozygous mutations in BBS1 and BBS4. RT-PCR and long-range genomic PCR analyses identified a new heterozygous mutation in BBS1, the deletion of exons 10 and 11. Thus, this patient was compound heterozygous for mutations in BBS1. Many studies have described digenic heterozygous mutations in BBS. However, undetected mutations might have existed in either one of the mutated genes.

Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome.

AIM: To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet-Biedl syndrome (BBS). MATERIALS AND METHODS: Individuals aged 12 years and older with BBS received once-daily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if <100 kg at baseline) continued into the 52-week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes. RESULTS: From February 2017 and February 2018, 10 individuals were screened; eight completed the 3-month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was -5.5% (90% CI, -9.3% to -1.6%; n = 8); change from baseline was -11.3% (90% CI, -15.5% to -7.0%; n = 8) at 6 months and -16.3% (90% CI, -19.9% to -12.8%; n = 7) at 12 months. All participants reported at least one treatment-emergent adverse event (AE), most commonly injection-site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points. CONCLUSIONS: Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS-associated obesity and hyperphagia.

Clinical, molecular genetics and therapeutic aspects of syndromic obesity.

Obesity has become a major health problem worldwide. To date, more than 25 different syndromic forms of obesity are known in which one (monogenic) or multiple (polygenic) genes are involved. This review gives an overview of these forms and focuses more in detail on 6 syndromes: Prader Willi Syndrome and Prader Willi like phenotype, Bardet Biedl Syndrome, Alström Syndrome, Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation syndrome and 16p11.2 (micro)deletions. Years of research provided plenty of information on the molecular genetics of these disorders and the obesity phenotype leading to a more individualized treatment of the symptoms, however, many questions still remain unanswered. As these obesity syndromes have different signs and symptoms in common, it makes it difficult to accurately diagnose patients which may result in inappropriate treatment of the disease. Therefore, the big challenge for clinicians and scientists is to more clearly differentiate all syndromic forms of obesity to provide conclusive genetic explanations and eventually deliver accurate genetic counseling and treatment. In addition, further delineation of the (functions of the) underlying genes with the use of array- or next-generation sequencing-based technology will be helpful to unravel the mechanisms of energy metabolism in the general population.

Renal transplantation in Bardet-Biedl Syndrome.

BACKGROUND: Renal anomalies are common in patients with Bardet-Biedl syndrome (BBS), a renal cystic ciliopathy with multi-systemic features. Renal transplantation is indicated in cases of end-stage renal disease (ESRD), but transplant centers may be hesitant to perform the necessary transplant in light of the multitude of metabolic comorbidities these patients often face with the potential to complicate outcomes. METHODS: Data from the Clinical Registry Investigating BBS (CRIBBS) were used to investigate renal transplant outcomes in the largest BBS cohort described to date. RESULTS: Of the 206 patients enrolled in the CRIBBS, 21 children (10.2 %; 16 girls, 5 boys; median age 8.4 years) had been diagnosed with ESRD. Renal transplantation was performed in 18 of these individuals between 1982 and 2015, including repeat transplantation in some cases, for a total of 22 kidneys. Overall graft survival was 81.6 % at 1 year post-transplantation, 75.7 % at 5 years, 59 % at 10 years, and 49.2 % at 25 years. Patient survival was 94.4 % at 1 year post-transplantation, 87.2 % at 8 years, and 79.3 % at 25 years. CONCLUSIONS: At a median follow-up time of 97 months, relatively few complications of renal transplantation were reported in the patients of this study. However, body mass index was significantly elevated in transplanted individuals compared to non-transplanted individuals participating in CRIBBS at the most recent follow-up. Although the frequency of obesity and other manifestations of the metabolic syndrome warrant meticulous management in this high-risk population, favorable long-term outcomes suggest that renal transplantation is a viable option for patients with BBS and ESRD.

Diabetes mellitus in Bardet Biedl syndrome.

PURPOSE OF REVIEW: Bardet Biedl syndrome (BBS) is a rare disease characterized by obesity and hyperphagia. Despite the very high prevalence of paediatric and adult obesity in this population, the prevalence of diabetes mellitus is not well described. RECENT FINDINGS: Studies in small and moderately large cohorts suggest a high prevalence of traditional risk factors for diabetes mellitus in people with BBS. People with BBS appear to have a high prevalence of insulin resistance and metabolic syndrome. Small cohort studies have identified high rates of sleep disordered breathing, including sleep apnoea syndrome. Recent research has characterized traditional behavioural risk factors such as sleep hygiene and physical inactivity in people with BBS. High rates of insufficient sleep and prolonged sedentary time suggest behavioural targets of interventions to treat or prevent diabetes mellitus. Hyperphagia, likely caused by defects in the hypothalamic melanocortin-4 receptor (MC4R) neuronal pathway, pose additional challenges to behavioural interventions to prevent diabetes mellitus. SUMMARY: Understanding the prevalence of diabetes mellitus and other metabolic disorders in people with BBS and the impact of traditional risk factors on glucose regulation are important to developing effective treatments in this population.

Potential amelioration of morbidity in patients with chromosomal anomalies: relevance to Bardet-Biedl syndrome.

Given the genetic basis of their disease, children with major chromosomal abnormalities including Bardet-Biedl syndrome (BBS) are generally considered to have a guarded prognosis with persistence or progression of disease manifestations. Although various therapeutic interventions are commonly used to control signs and symptoms of illness, parents of BBS children are usually cautioned against hoping for sustained improvement. A case of a 21-month-old girl, diagnosed with BBS, manifesting signs of worsening visual impairment, obesity, irascible and disordered behaviour, as well as developmental delay, is presented. After initial evaluation suggested specific biochemical deficiencies, nutritional status correction was undertaken and the patient's signs and symptoms subsequently resolved over the course of several months. To the authors' knowledge, this is the first case report of sustained resolution of all disease manifestations in the face of previously deteriorating health in a young child with this major chromosomal abnormality. It appears that biochemical imbalances and insufficiencies resulting from abnormal metabolism and excretion are potentially amenable to extraordinary dietary supplementation, with partial or complete resolution of clinical abnormalities. It is recommended that all children with chromosomal abnormalities have biochemical and nutritional status evaluation with correction of disordered biochemistry as is possible.

Clinical manifestations of hereditary cystic kidney disease.

Genetic mutations of discrete loci are the cause of a diverse array of polycystic kidney disease syndromes which present in distinct, as well as overlapping, phenotypic and hereditary patterns. Since molecular diagnostics are not currently a feasible clinical tool for the diagnosis of most cystic kidney diseases, physicians must rely upon their clinical acumen and knowledge base in order to identify these patients. The goal of this manuscript is to review the hereditary patterns, basic epidemiology, and phenotypic features of the most common of the cystic renal diseases so as to increase the awareness of these renal diseases among practicing physicians. Specifically, the genetic and phenotypic features of autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, nephronopthisis-medullary cystic kidney disease complex, Bardet-Biedl syndrome, and oral-facial-digital syndrome type 1 will be reviewed.

[Bardet-Biedl syndrome]. / Le syndrome de Bardet-Biedl.

Bardet-Biedl syndrome (BBS) is a ciliopathy causing multivisceral abnormalities. Its prevalence in Europe is from 1/125,000 to 1/175,000. This disorder is defined by a combination of clinical signs: obesity, pigmentary retinopathy, post-axial polydactyly, polycystic kidneys, hypogenitalism, and learning disabilities, many of which appearing after several years of evolution. Individual clinical phenotype is highly variable. Most signs are present in a majority of patients but only pigmentary retinopathy is constant after infancy. There are many other associated minor clinical signs including diabetes, blood hypertension, congenital cardiopathy or Hirschsprung disease. This broad clinical spectrum is associated to a great genetic heterogeneity, with mainly an autosomal recessive transmission and, sometimes cases of oligogenism. To date, mutations in 12 different genes (BBS1 to BBS12) are responsible for this phenotype. These genes code for proteins involved in the development and function of primary cilia. Absent or non functional BBS proteins affect cilia in certain organs such as kidney or eye. However, some symptoms are still not clearly related to cilia dysfunction. BB syndrome has to be recognized because a molecular diagnosis is possible and will lead to familial genetic counseling and possibly prenatal diagnosis. Patients with BBS will need a multidisciplinary medical care. The renal abnormalities are the main life-threatening features because they can lead to end-stage renal failure and renal transplantation. Retinal dystrophy leading to progressive vision loss, moderate mental retardation, and obesity will affect social life of these patients.

A population-based description of familial clustering of Hirschsprung disease.

BACKGROUND: Familial recurrence of Hirschsprung disease (HSCR) is well documented, and risk estimates for relatives have been reported from various populations. We describe the familial clustering of HSCR cases using well-established unbiased familial aggregation techniques within the context of a population genealogy. METHODS: Patients included 264 HSCR cases identified using ICD-9 diagnosis coding from the two largest healthcare providers in Utah who also had linked genealogy data. The GIF statistic was used to identify excess familial clustering by comparing average relatedness of cases to matched controls. In addition, relative risks (RRs) of HSCR in relatives of cases were estimated using age-, sex- and birthplace-matched disease rates, and for several diseases frequently associated with HSCR (Down syndrome, multiple endocrine neoplasia IIa, central hypoventilation syndrome, Bardet-Biedl syndrome, ventricular and atrial septal defect). RESULTS: Significant excess relatedness was observed for all HSCRs (p<1e-3). Significant RRs for HSCR were observed for first-, second-, and fourth-degree relatives of cases (RR=12.0, 10.0, and 4.6, respectively). Significant elevated risks of Down syndrome, Bardet-Biedl syndrome, and atrial and ventricular septal defects were observed for HSCR cases. CONCLUSION: This population-based survey of HSCR provides confirmation of a genetic contribution to HSCR disease and presents unbiased risk estimates that may have clinical value in predicting recurrence. LEVEL OF EVIDENCE RATING: Prognosis study, level II.

The Endocrine and Metabolic Characteristics of a Large Bardet-Biedl Syndrome Clinic Population.

Context: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder in which previous reports have described obesity and a metabolic syndrome. Objective: We describe the endocrine and metabolic characteristics of a large BBS population compared with matched control subjects. Design: We performed a case-control study. Setting: This study was performed at a hospital clinic. Patients: Study patients had a clinical or genetic diagnosis of BBS. Main Outcome Measurements: Our study determined the prevalence of a metabolic syndrome in our cohort. Results: A total of 152 subjects were studied. Eighty-four (55.3%) were male. Mean (± standard deviation) age was 33.2 ± 1.0 years. Compared with age-, sex-, and body mass index-matched control subjects, fasting glucose and insulin levels were significantly higher in subjects with BBS (glucose: BBS, 5.2 ± 1.2 mmol/L vs control, 4.9 ± 0.9 mmol/L, P = 0.04; insulin: BBS, 24.2 ± 17.0 pmol/L vs control, 14.2 ± 14.8 pmol/L, P < 0.001). Serum triglycerides were significantly higher in subjects with BBS (2.0 ± 1.2 mmol/L) compared with control subjects (1.3 ± 0.8 mmol/L; P < 0.001), but total cholesterol, high-density lipoprotein, and low-density lipoprotein were similar in both groups. Systolic blood pressure was higher in the BBS group (BBS, 135 ± 18 mm Hg vs control subjects, 129 ± 16 mm Hg; P = 0.02). Alanine transaminase was raised in 34 (26.8%) subjects with BBS, compared with five (8.9%) control subjects (P = 0.01). The rate of metabolic syndrome, determined using International Diabetes Federation criteria, was significantly higher in the BBS group (54.3%) compared with control subjects (26% P < 0.001). Twenty-six (19.5%) of male subjects with BBS were hypogonadal (serum testosterone, 9.9 ± 5.3 mmol/L), but significant pituitary abnormalities were uncommon. Subclinical hypothyroidism was present in 24 of 125 (19.4%) patients with BBS, compared with 3 of 65 (4.6%) control subjects (P = 0.01). Conclusions: Insulin resistance and the metabolic syndrome are increased in adult patients with BBS compared with matched control subjects. Increased subclinical hypothyroidism in the BBS cohort needs further investigation.

[Patho-physiology of renal dysfunction in Bardet-Biedl Syndrome]. / DIl coinvolgimento renale nella sindrome di Bardet-Biedl.

Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder with renal and extra-renal involvement. The wide spectrum of clinical manifestations is associated to the high genetic heterogeneity. To date 21 genes have been identified in humans and the majority of them encode proteins located on the basal body of the primary cilium. For this reason the disease is has been included among the 'ciliopathies'. The renal involvement is extremely heterogeneous in BBS and is considered the main cause of morbidity and mortality. Recent evidences have suggested that mutations in BBS6, 10 and 12 are associated with a more severe renal dysfunction. The most common renal dysfunction is the urine concentrating defect, even though the underlying mechanism is not completely known. Recently we have demonstrated that hyposthenuria in BBS patients has a renal origin, and depends on desmopessin resistance. The majority of hyposthenuric BBS patients have a combined defect to both concentrate and dilute the urine. The combined defect is associated with a blunted increased urine Aquaproine-2 (u-AQP2) excretion in antidiuresis. A ccordingly, in vitro BBS10 silencing prevented AQP2 trafficking to the apical plasma membrane. However, after long term water restriction hyposthenuric BBS patients showed the same u-AQP2 excretion compared with controls, suggesting that other mechanisms are implicated into the pathogenesis of hyposhtenuria. The complete molecular mechanism underlying hyposhtenuria remains largely unknown in BBS. Whether this defect may represent a predictor factor for poor renal outcome remains to be elucidated.

Bardet Biedl syndrome in South Africa: A single founder mutation.

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.

[Algorithm for the molecular analysis of Bardet-Biedl syndrome in Spain]. / Algoritmo para el estudio molecular del síndrome de Bardet-Biedl en España.

BACKGROUND AND OBJECTIVE: Bardet-Biedl syndrome (BBS) is a multisystemic genetic disorder, which is not widespread among the Caucasian population, characterized by a highly variable phenotype and great genetic heterogeneity. BBS belongs to a group of diseases called ciliopathies, caused by defects in the structure and/or function of cilia. Due to the diagnostic complexity of the syndrome, the objective of this study was to analyse our whole group of patients in order to create an algorithm to facilitate the routine molecular diagnosis of BBS. We also calculated several epidemiological parameters in our cohort. PATIENTS AND METHOD: We analysed 116 BBS patients belonging to 89 families from the whole Spanish geography. All probands fulfilled diagnosis criteria established for BBS. For this, we used: genotyping microarray, direct sequencing and homozygosis mapping (in consanguineous families). RESULTS: By means of the different approaches, it was possible to diagnose 47% of families (21% by genotyping microarray, 18% by direct sequencing of predominant BBS genes, and 8% by homozygosis mapping). With regard to epidemiological data, a prevalence value of 1:407,000 was obtained for BBS in Spain, and a sex ratio of 1.4:1 (men:women). CONCLUSIONS: The proposed algorithm, based on the analysis of predominant BBS genes combined with homozygosis mapping, allowed us to confirm the molecular diagnosis in a significant percentage of families with clinically suspected BBS. This diagnostic algorithm will be useful for the improvement of the efficiency of molecular analysis in BBS.

The First Nationwide Survey and Genetic Analyses of Bardet-Biedl Syndrome in Japan.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by central obesity, mental impairment, rod-cone dystrophy, polydactyly, hypogonadism in males, and renal abnormalities. The causative genes have been identified as BBS1-19. In Western countries, this disease is often reported, but remains undiagnosed in many patients until later in life, while only a few patients with no mutations identified have been reported in Japan. We thus conducted the first nationwide survey of BBS in Japan by sending questionnaires to 2,166 clinical departments with board-certified specialists and found 7 patients with clinically definite BBS. We performed exome analyses combined with analyses of mRNA and protein in these patients. We identified 2 novel mutations in the BBS5 gene (p.R89X and IVS7-27 T>G) in 2 sibling patients. The latter mutation that resided far from the authentic splicing site was associated with skipping of exon 8. We also found 3 previously reported mutations in the BBS2 (p.R413X and p.R480X) and BBS7 (p.C243Y) genes in 2 patients. To our knowledge, a nationwide survey of BBS has not been reported in any other country. In addition, this is the first study to identify genetic alterations in Japanese patients with BBS. Our results indicate that BBS in Japan is genetically heterogeneous and at least partly shares genetic features with BBS in other countries.

Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterised by retinal dystrophy, obesity, post-axial polydactyly, renal dysfunction, learning difficulties and hypogonadism. Many associated minor features can be helpful in making a diagnosis and are important in the clinical management of BBS. The diagnosis is based on clinical findings and can be confirmed by sequencing of known disease-causing genes in 80% of patients. BBS genes encode proteins that localise to the cilia and basal body and are involved in cilia biogenesis and function. Mutations lead to defective cilia accounting in part for the pleiotropic effects observed in BBS. We provide an overview of BBS including the clinical findings, current understanding of cilia biology, and a practical approach to diagnosis, genetic counselling and up-to-date management.

Roux-en-Y gastric bypass in an adolescent patient with Bardet-Biedl syndrome, a monogenic obesity disorder.

Bardet-Biedl syndrome (BBS) is a rare genetic disorder characterized by a wide range of phenotypic variability and associated with the development of life-threatening obesity. Birth weight tends to be normal, but rapid weight gain begins after the first year, probably due to polyphagia rather than abnormalities in energy metabolism. A morbidly obese 16-year-old male patient with BBS was referred to our institution, after nonsurgical methods of weight control had failed, for surgical treatment of his obesity. His preoperative body mass index (BMI) was 52.28 kg/m(2) (height, 1.84 m; weight, 177 kg) and was above the 99th centile for age and gender. The patient underwent laparoscopic Roux-en-Y gastric bypass (RYGBP). The postoperative period was uneventful. Three and a half years after the operation, the patient's weight has decreased to 118 kg (BMI, 34.85 kg/m(2)), while significant improvement in his hypertension, hyperuricemia, and mobility has been noted. In our BBS patient, RYGBP proved to be safe and effective; nevertheless, longer follow-up is required to evaluate the weight loss durability and to assess the lasting beneficial effect of surgical intervention on genetically determined co-morbidities.

Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy.

Bardet-Biedl syndrome (BBS) is a multisystemic disorder typified by developmental and progressive degenerative defects. A combination of genetic, in vitro, and in vivo studies have highlighted ciliary dysfunction as a primary cause of BBS pathology, which has in turn contributed to the improved understanding of the functions of the primary cilium in humans and other vertebrates. Here we discuss the evidence linking the clinical BBS phenotype to ciliary defects, highlight how the genetic and cellular characteristics of BBS overlap with and inform other ciliary disorders, and explore the possible mechanistic underpinnings of ciliary dysfunction.

A novel founder BBS1 mutation explains a unique high prevalence of Bardet-Biedl syndrome in the Faroe Islands.

BACKGROUND/AIM: Bardet-Biedl syndrome is a multiorgan disease presenting with retinitis pigmentosa leading to blindness. The aim of the study was to investigate the genetic background of Bardet-Biedl syndrome in the Faroe Island. It was hypothesised that a common genetic background for the syndrome would be found. METHODS: Patients were identified from the files of the Retinitis Pigmentosa Register at the National Eye Clinic, Denmark. The diagnosis of Bardet-Biedl syndrome was verified from medical files. Mutational screening of BBS1, BBS2, BBS4, MKKS and BBS10 was done by denaturing high-performance liquid chromatography. RESULTS: Out of 13 prevalent cases in the Faroe Islands, 10 patients from nine families were included. A novel splice site mutation in BBS1, c.1091+3G>C, was identified, and this was predicted to affect protein function by skipping 16 amino acids. Nine patients were homozygous for this mutation, while one patient was compound heterozygous with a recurrent BBS1 mutation, p.Met390Arg. The patients presented with severe ophthalmic phenotypes, while the systemic manifestations of the disease were apparently milder. CONCLUSION: A novel BBS1 mutation was identified, most probably a founder mutation, further confirming the Faroe Islands as a genetic isolate. The phenotypic expression of the Faroese patients suggests that different mutations in BBS1 affect various organs differently.