Twenty-one disease-causing genes have been identified to date. It is one of the most well-studied conditions in the family of diseases caused by defective cilia collectively known as ciliopathies. In this review, we provide an update on diagnostic developments, clinical features, and progress in the management of Bardet—Biedl syndrome. Advances in diagnostic technologies including exome and whole genome sequencing are expanding the spectrum of patients who are diagnosed with Bardet—Biedl syndrome and increasing the number of cases with diagnostic uncertainty.

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Twenty-one disease-causing genes have been identified to date. It is one of the most well-studied conditions in the family of diseases caused by defective cilia collectively known as ciliopathies.

In this review, we provide an update on diagnostic developments, clinical features, and progress in the management of Bardet—Biedl syndrome. Advances in diagnostic technologies including exome and whole genome sequencing are expanding the spectrum of patients who are diagnosed with Bardet—Biedl syndrome and increasing the number of cases with diagnostic uncertainty.

As a result of the diagnostic developments, a small number of patients with only one or two clinical features of Bardet—Biedl syndrome are being diagnosed. Our understanding of the syndrome-associated renal disease has evolved and is reviewed here. Novel interventions are developing at a rapid pace and are explored in this review including genetic therapeutics such as gene therapy, exon skipping therapy, nonsense suppression therapy, and gene editing.

Other non-genetic therapies such as gene repurposing, targeted therapies, and non-pharmacological interventions are also discussed. Bardet—Biedl syndrome BBS , sometimes known as Laurence—Moon—Bardet-Biedl syndrome, is a rare autosomal recessive ciliopathy characterized by rod-cone dystrophy, learning difficulties, polydactyly, obesity, genital malformations, and renal abnormalities. In the s, a family with retinitis pigmentosa, obesity, and intellectual impairment was described by doctors Laurence and Moon.

The affected family members later went on to develop a spastic paraparesis. In and , respectively, doctors Bardet and Biedl independently described two families with obesity, retinitis pigmentosa, and polydactyly. From , the syndrome was known as Laurence—Moon—Bardet—Biedl syndrome, but there was disagreement as to whether they were the same entity.

Later, it was considered as two entities, Laurence—Moon and Bardet—Biedl syndromes, but mutations in known BBS genes have been seen in families with both syndromes 1 , 2. Today, it is most usually known as BBS. It is a pleiotropic disorder and has a prevalence of around , in North America and Europe, but it is significantly more common in certain isolated communities including Newfoundland , 2 and Kuwaiti Bedouins 1: 13, 3 , 4.

Table 1 outlines the 21 BBS genes. Bardet—Biedl syndrome is a pleiotropic disorder and diagnosis is based on the presence of at least four major features or three major features and at least two minor features in accordance with the diagnostic criteria published by Beales et al.

Figure 1 demonstrates the clinical features associated with BBS and highlights the relative frequencies at which these features are observed. Figure 1. Clinical and diagnostic features of Bardet—Biedl syndrome. A—D Typical facial features are often subtle and not always present. Typical facial features include malar hypoplasia, a depressed nasal bridge, deep set eyes, and retrognathia.

E Brachydactyly. F Dental crowding. G High palate. H Rod-cone dystrophy. At least four major features or three major and two minor features are required to make a clinical diagnosis. Informed consent was obtained and republished with permission 4.

Molecular confirmation of BBS has evolved over the last decade from targeted sequencing of common genetic variants, including the common BBS1 p. MR, BBS2 p. Y24X, BBS2 p.

RX, and BBS10 c. The age at which patients are diagnosed is extremely variable and is driven by the age of onset of symptomatic rod-cone dystrophy. While this may manifest in infancy, it is more usually seen between the ages of 5 and 10 years of age and typically presents with night blindness 9. Isolated polydactyly at birth or obesity, generally seen from infancy, do not usually prompt referral. Siblings of affected children are generally diagnosed earlier.

Antenatal diagnosis is extremely rare in the absence of a family history, but BBS may be suspected from the identification of echogenic kidneys and polydactyly on ultrasound scanning. Children presenting with renal anomalies or renal failure may be diagnosed earlier than those without, but there are insufficient data to confirm this.

A subset of individuals present with isolated rod-cone dystrophy with notable absence of other BBS-related features and are often diagnosed in adulthood. These individuals are now being picked up because of the introduction of panel-based genetic testing and major diagnostic studies such as the UK , genomes project 10 and the Deciphering Developmental Disorders exome study They were previously overlooked as there are many causes of rod-cone dystrophy, and it was not understood that BBS genes could cause this feature in isolation.

Currently, diagnostic gene panels are the diagnostic tool of choice. The use of whole exome sequencing WES and whole genome sequencing WGS may increase coverage, aid in the discovery of novel genes, and allow for the identification of non-coding variants. However, along with increased expense, disadvantage of the more advanced diagnostic sequencing techniques is the identification of pathogenic variants in non-BBS genes and of variants of unknown significance VUS in BBS genes Variable expressivity is the hallmark of BBS 8 ; patients with the same genotype and even siblings frequently manifest symptoms differently.

As a result, although genotype—phenotype correlations exist on a population basis, it is not possible to make individual predictions about symptomatic manifestations As a group, patients with mutations in BBS1 are usually less severely affected than patients with mutations in other BBS genes.

On average, they develop visual deterioration later in life 14 , are less likely to develop renal disease 13 , and more likely to have a better endocrine biochemical profile 15 with a lower prevalence of metabolic syndrome 16 , It is not possible to delineate if this is a consequence of the common missense mutation BBS1 p. Suggestion that BBS would be a candidate for triallelic inheritance, whereby a third mutation is required to either manifest the condition or adding mutational load, has gathered limited evidence 18 — In practice, the phenotypic variability observed in patients with the same genotype and within families is likely to reflect a complex interplay between multiple genetic factors and environmental influences.

Bardet—Biedl syndrome has classically been associated with polycystic kidney disease, a typical feature of ciliopathies with renal manifestations 13 , 16 , 23 — The majority of patients who develop end-stage renal disease do so in early childhood before the age of 5 , and in most cases, deterioration is rapid with frequent requirement for dialysis within the first year of life Some patients develop sudden renal failure in adulthood for unknown reasons, and a further group of patients develop end-stage kidney disease as a result of comorbidities including type 2 diabetes and hypertension The risk of type 2 diabetes relates to obesity and is treated using standard protocols.

Many patients with structural renal abnormalities do not go on to develop functional renal disease The molecular mechanistic pathways leading to renal disease in BBS remain unelucidated It has been suggested that aberrant mTOR signaling may contribute to the development of cystic kidney disease Another theory proposes that ciliary dysfunction leads to aberrant non-canonical Wnt signaling and planar cell polarity, which may contribute to the development of cysts Molecular evidence supporting these theories remains limited.

Furthermore, they do not explain why only some patients develop renal dysplasia or indeed the heterogeneous types of renal disease developed by patients. Bardet—Biedl syndrome is currently treated symptomatically focusing in particular on aggressive management of diabetes, hypertension, and metabolic syndrome to minimize the secondary impact that these conditions have on vulnerable organ systems already affected by BBS, in particular the eyes and kidneys Weight management is a continual struggle for the majority of patients Some elect to have bariatric surgery 32 while others take antiobesity medication, but for the majority of patients, dietetic input provides the safest and most effective weight loss strategy In the UK, patients who attend the national BBS clinics are invited to attend a multidisciplinary clinic for annual review by a geneticist, ophthalmologist, nephrologist, endocrinologist, psychologist, dietitian, speech and language therapist, nurse, and a patient support group representative.

This provides a platform for regular review and individualized risk assessment in particular with reference to renal and endocrine deterioration. All patients are genotyped using a service-developed diagnostic gene panel. The clinic also provides an opportunity for research into the natural progression of BBS, and it is expected that patients will eventually be stratified according to genotype and their need for clinical follow-up.

The last decade has seen significant advances in the development of therapeutic modalities, which could potentially be applicable to patients with BBS and related ciliopathies. However, the large number of disease-causing genes and private mutations, which are those seen in only a single family, present a unique challenge in developing genetic therapies for BBS Figure 2 outlines potential future therapies, which are likely to benefit patients with BBS in the future.

Figure 2. Future interventions and stage in the pharmacological development process. Genetic therapies and other pharmacological interventions are under development for BBS. Dark blue arrows demonstrate the stage to which BBS-specific interventions have been developed.

Other ciliopathy relevant developments are indicated in light blue. The last column indicates the percentage of BBS patients who could benefit from this type of intervention.

A particular focus for therapeutic intervention in the ciliopathies has been the development of therapy for rod-cone dystrophy 34 — The eye offers an attractive organ for therapeutic intervention in BBS due to the ease of access, the presence of a control other eye, the small amount of tissue that needs to be infiltrated, and a window of opportunity to develop treatment as patients typically do not develop symptoms before mid to late childhood Novel disease models are being generated with the potential to develop in vitro organ systems for the assessment of new therapies.

A promising development is the generation of induced pluripotent stem cells 38 — These cells are generated when adult cells are reprogrammed and subsequently differentiated into another cell type through the addition of growth factors A number of cell types have been used for reprogramming including dermal fibroblasts 44 , renal epithelial cells 45 , keratinocytes 46 , and peripheral blood cells Urine-derived renal epithelial cells have been used to model ciliopathies, such as Joubert syndrome to assess the effect of potential therapeutics 48 , 49 and BBS to derive mechanistic insights into disease pathogenesis unpublished data.

This is a particularly attractive model for many ciliopathies including BBS as it is non-invasive and offers an organ-specific relevant disease model.

To our knowledge, currently, there are no efforts in progress to develop genetic therapies targeted to the renal manifestations of BBS. This is likely to be a function of a number of issues including that the onset of renal manifestations is often antenatal precluding a therapeutic window of opportunity. Furthermore, the natural history of renal disease in BBS is not well understood, and the cause of renal disease can be both primary e.

In addition, the kidney is more difficult to target with genetic therapies but may prove to be a more amenable target for pharmacological therapies. Traditional gene replacement therapy has achieved significant success in the treatment of ciliopathy-related eye diseases including Usher syndrome and Leber congenital amaurosis in recent years 50 — The premise involves the generation of viral or non-viral vectors carrying a wild-type gene of choice with the aim of integrating the gene into the host genome.

The highest chance of success is achieved in diseases where only a small amount of healthy gene expression is required to generate a phenotypic effect A major challenge in developing genetic therapies for BBS is the generation of a long lasting therapy. A successful example of this is the retinal gene therapy Luxturna , which has been successfully developed for RPEassociated Leber congenital amaurosis.

It is likely to obtain approval from the Food and Drug Administration FDA in as the first gene therapy for ocular disease. Extensive optimization was required before RPE65 gene therapy could be launched for FDA approval due to concerns about the sustainability and long-term maintenance of visual function 36 , 37 , Work on retinal gene replacement therapy for BBS is ongoing in animal models, and recent efforts were published demonstrating encouraging results in knock-in mouse models with the most common genotype in humans BBS1 p.



Bardet–Biedl syndrome

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Laurence–Moon syndrome

Bardet—Biedl syndrome BBS is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized principally by obesity , retinitis pigmentosa , polydactyly , hypogonadism , and kidney failure in some cases. Bardet—Biedl syndrome is a pleiotropic disorder with variable expressivity and a wide range of clinical variability observed both within and between families. The main clinical features are rod—cone dystrophy , with childhood-onset visual loss preceded by night blindness; postaxial polydactyly ; truncal obesity that manifests during infancy and remains problematic throughout adulthood; specific learning difficulties in some but not all individuals; male hypogenitalism and complex female genitourinary malformations; and renal dysfunction, a major cause of morbidity and mortality. There is a wide range of secondary features that are sometimes associated with BBS [3] including [4].

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