Managing Bardet-Biedl Syndrome-Now and in the Future

Abstract

Bardet-Biedl syndrome is a rare autosomal recessive multisystem disorder caused by defects in genes encoding for proteins that localize to the primary cilium/basal body complex. 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.

Keywords: Bardet–Biedl syndrome; drug repurposing; genetic therapies; genome editing; pharmacogenomics; targeted therapies.

Figure 1

Clinical and diagnostic features of Bardet–Biedl syndrome. (i) Clinical features associated with 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. (ii) Diagnostic features of Bardet–Biedl syndrome. 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).

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. BBS, Bardet–Biedl syndrome; LCA, leber congenital amaurosis; PCD, primary ciliary dyskinesia; RP, retinitis pigmentosa; US, Usher syndrome.