Bardet-Biedl Syndrome (BBS) is a rare, genetically heterogeneous ciliopathy that affects multiple organ systems.
Diagnostic Criteria
Diagnosis is still based on criteria defined in 1999 (Beales, 1999) and made when a patient has either:
- Four major clinical features, or
- Three major features and two minor features
Major criteria:
- Rod-cone dystrophy (typically presents by 8 years old)
- Early-onset obesity (usually between ages 2–5)
- Postaxial polydactyly
- Renal anomalies or dysfunction
- Cognitive impairment
- Hypogonadism
Minor criteria:
- Speech or developmental delay
- Diabetes
- Dental anomalies
- Ataxia
- Congenital heart defects
- Syndactyly or brachydactyly
- Anosmia/hyposmia
- Genitourinary anomalies
When to Consider Testing
Genetic testing should be considered in individuals with:
- Onset of obesity before 5 years of age
- Obesity combined with developmental delay or hyperphagia
- Presence of polydactyly, renal anomalies, or genital abnormalities
- Family history of syndromic obesity or early-onset vision loss
Recommended Genetic Tests
1. BBS Gene Panels:
Covers all known BBS-related genes (>20). Useful for confirmation and subtype identification.
2. Whole Exome Sequencing (WES):
Recommended when panel testing is negative or if other syndromic features are present.
3. Targeted Variant Testing:
Useful for relatives of patients with a known BBS-causing variant.
Free or Low-Cost Testing Resources
- UncoveringRareObesity.com offers a no-cost genetic panel for individuals with early-onset obesity and suspected syndromic features. (US only)
- Commercial labs such as Invitae, GeneDx, Centogene, and Blueprint Genetics offer clinically validated BBS panels, often insurance-covered.
Genetic Counseling
Genetic counseling is recommended for:
- Families with a child diagnosed with BBS
- Carrier testing in siblings or parents
- Family planning and reproductive options, including preimplantation genetic diagnosis (PGD)
BBS is inherited in an autosomal recessive pattern. Each sibling of an affected individual has a 25% chance of being affected.
Over 80% of BBS cases have an identifiable pathogenic variant.
Confirmatory and Supportive Evaluations
Following a positive genetic result, baseline evaluations should include:
- Ophthalmology exam (dilated retinal exam ± ERG)
- Renal ultrasound and yearly creatinine
- Developmental assessment
- Endocrine evaluation (puberty status, insulin resistance)
- Cardiology if congenital heart disease is suspected
Notes on Genotype–Phenotype Correlation
- BBS1 variants are associated with milder phenotypes, including later-onset obesity and less renal involvement.
- BBS10 and BBS12 are often associated with more severe metabolic complications and earlier obesity.
- Complete loss-of-function (e.g., nonsense, frameshift) mutations are generally linked with more severe disease.
Differential Diagnosis
Consider other syndromes when testing for BBS:
| Syndrome | Key Features | Gene(s) | Inheritance |
|---|---|---|---|
| Alström Syndrome | Obesity, retinal dystrophy, hearing loss, cardiomyopathy | ALMS1 | AR |
| Prader-Willi Syndrome | Infantile hypotonia, hyperphagia onset ~8 y/o, behavioral phenotype | 15q11-q13 (paternal) | AD |
| Meckel Syndrome | Lethal malformations, occipital encephalocele | CEP290, others | AR |
| Leptin/LEPR Deficiency | Early obesity, immune issues | LEP, LEPR | AR |
| MC4R Deficiency | Non-syndromic early-onset obesity | MC4R | Co-dominant |
Summary steps
| 1 | Identify clinical features based on diagnostic criteria |
| 2 | If available, obtain a BBS gene panel or whole-exome sequencing |
| 3 | Obtain genetics and multidisciplinary care |
| 4 | Evaluate organ systems |
| 5 | Counseling and long-term monitoring |
REFERENCES
Shoemaker A. Bardet-Biedl syndrome: A clinical overview focusing on diagnosis, outcomes and best-practice management. Diabetes Obes Metab. 2024;26(S2):25–33. doi:10.1111/dom.15494
Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: Results of a population survey. J Med Genet. 1999;36(6):437–446.