BBSUK

What is Bardet-Biedl Syndrome?

Bardet-Biedl Syndrome is a rare, recessively inherited ciliopathy which affects approximately 1 in 100,000 babies born. Features of the syndrome include rod-cone dystrophy, a progressive eye disorder that leads to blindness, characterised by tunnel vision and night blindness; obesity; renal abnormalities; developmental delay; speech and language difficulties; extra fingers and/or toes and learning difficulties. The variability in presentation and severity of the syndrome together with the rarity of the condition can lead to delayed diagnosis and a lack of adequate local health care. There are around 560 affected individuals known to us in the UK.

There is at present no cure for Bardet-Biedl Syndrome. Patients have access to NHS specialised multi-disciplinary clinics held in four centres in London and Birmingham. Bardet-Biedl Syndrome UK are third-sector partners in this service.

Diagnosis

Beales et al (1999 and 2001) suggest that the presence of four primary features or three primary features plus two secondary features is necessary for a clinical diagnosis of Bardet-Biedl Syndrome. Not all of the features are always present in those diagnosed as having BBS and each one can vary in severity and appearance.

Primary Features

  • Rod-cone dystrophy
  • Polydactyly
  • Obesity
  • Learning disabilities
  • Hypogonadism in males
  • Renal anomalies

Secondary Features

  • Speech delay/disorder
  • Developmental delay
  • Brachydactyly
  • Polyuria/polydipsia
  • Ataxia
  • Poor co-ordination
  • Diabetes mellitus
  • Left ventricular hypertrophy
  • Hepatic fibrosis

In most cases of BBS, both parents carry a normal gene and a faulty, recessive gene. Although the parents have one copy of the faulty gene and are called carriers of the disease, they are unaffected by the presence of the faulty gene. For a recessive disease to occur, a child has to inherit two faulty copies of the gene; one from each parent. The child from each pregnancy has a 1 in 4 chance of being affected. If a new born child is not affected then there is a 2 in 3 chance that he/she will be a carrier of the faulty gene for BBS. As the syndrome is rare, a gene carrier is unlikely to have affected children unless their partner is also a carrier. This risk of encountering another carrier increases if people marry close relatives. As some BBS genes are more common than others, there is variation in the frequency with which they are being carried, known or unknown, in the population. For the most common BBS genes, BBS1 and BBS10, the frequency is estimated to be 1 in 250, whereas for a rarer gene such as BBS9, the frequency is closer to 1 in 820.

To date, (2020) mutations in 22 BBS genes have been identified in 85% of BBS patients. It is known that there are still more genes to find since not all patients have an identified mutation in any of these identified BBS genes, indicating that these patients must have mutations in other genes. Some genes are more common than others; a quarter of patients have mutations in BBS1 and another quarter have mutations in BBS10. However, patients who carry mutations in the same BBS gene can display quite different symptoms of the syndrome: one might have extra digits at birth whereas another person with an identical mutation may not have extra digits at all. It is hoped that comprehensive genetic testing will improve predictions about disease progression in the future.

Mutations in BBS genes cause changes in the proteins that are needed for the correct functioning of a particular part of the cell called a primary cilium. For this reason, BBS has been categorized medically as a ciliopathy. Ciliopathies are a range of human disease syndromes all caused by defects in primary cilia function. Examples of other ciliopathies include Alström Syndrome, Primary Ciliary Dyskinesia, Polycystic Kidney Disease, some forms of Retinitis Pigmentosa, Nephronophthisis, Joubert Syndrome and Meckel Syndrome, which have overlapping symptoms, all caused by defects in cilia proteins. Cilia are long thin, hair-like projections that stick out of the surface of a cell. There are two types of cilium, motile and non-motile or primary cilia (also called sensory cilia). Many cell types in the body rely on having a fully functional primary cilium. Important examples include the retinal photoreceptor in the eye, and cells in the kidney. The scientific community is trying to understand exactly what roles the BBS proteins play in cilia formation and function.
Where BBS is confirmed genetically, a simple carrier test is possible in at-risk adult relatives (e.g. siblings) to help determine their own risk of having affected children if their partner is also a carrier. Knowledge of the BBS mutations can also provide the basis for prenatal screening tests, should parents need to know in early pregnancy if the foetus is affected.
Where both parents are carriers of a change in the same BBS gene, every pregnancy has a 1 in 4 risk of the child having Bardet-Biedl Syndrome. If the genetic changes are known in the parents, there are several options available to them, should they wish to have more children.
Couples who are already pregnant may consider prenatal testing (e.g. chorionic villus sampling/amniocentesis). It involves testing either the tissue or fluid around the baby in early to mid pregnancy (10-16 weeks). There is a small risk to the pregnancy with prenatal testing; couples who wish to pursue this option should discuss it with their geneticist and obstetrician.
A couple can be referred to be considered for PGD via a clinician provided that they fulfil a number of criteria. These can vary between NHS centres, however common requirements are that they do not already have a healthy child and that they do not smoke. Couples who wish to pursue this route should contact their GP or geneticist. Couples who are not interested in either of these options, or do not know the genetic change that has caused BBS may opt to have a detailed scan throughout pregnancy to assess if there is evidence that the baby is affected. This should be done in a specialist centre by an ultrasonographer who is familiar with the features associated with BBS. Features of BBS may be difficult to pick up before 20 weeks gestation and, as already mentioned, may not be present in all babies with BBS.
Those who have BBS, who wish to have children, may also have several options available to them, including the options outlined above. The first step is for the partner of the person who has BBS to be tested for carrier status, to determine whether he or she carries the same change in the same gene. The children of a BBS affected parent will all be carriers of the affected gene, but will not have the syndrome provided that the other parent does not have any changes in the same gene. If the other parent is a carrier of a change in the same gene, then each child has a 50% chance of having the syndrome. If both parents have BBS, then all children will be affected with BBS.