Meta-analysis of genotype-phenotype associations in Bardet-Biedl syndrome uncovers differences among causative genes

Hum Mutat. 2019 Nov;40(11):2068-2087. doi: 10.1002/humu.23862. Epub 2019 Jul 29.


Bardet-Biedl syndrome (BBS) is a recessive genetic disease causing multiple organ anomalies. Most patients carry mutations in genes encoding for the subunits of the BBSome, an octameric ciliary transport complex, or accessory proteins involved in the BBSome assembly or function. BBS proteins have been extensively studied using in vitro, cellular, and animal models. However, the molecular functions of particular BBS proteins and the etiology of the BBS symptoms are still largely elusive. In this study, we applied a meta-analysis approach to study the genotype-phenotype association in humans using our database of all reported BBS patients. The analysis revealed that the identity of the causative gene and the character of the mutation partially predict the clinical outcome of the disease. Besides their potential use for clinical prognosis, our analysis revealed functional differences of particular BBS genes in humans. Core BBSome subunits BBS2, BBS7, and BBS9 manifest as more critical for the function and development of kidneys than peripheral subunits BBS1, BBS4, and BBS8/TTC8, suggesting that incomplete BBSome retains residual function at least in the kidney.

Keywords: BBS; BBSome; Bardet-Biedl syndrome; ciliopathy; genotype-phenotype; kidney disease; meta-analysis; rare disease.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / genetics
  • Bardet-Biedl Syndrome / diagnosis*
  • Bardet-Biedl Syndrome / genetics*
  • Cognitive Dysfunction / genetics
  • Congenital Abnormalities / genetics
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Genotype*
  • Humans
  • Kidney / abnormalities
  • Kidney Diseases / congenital
  • Kidney Diseases / genetics
  • Mutation
  • Penetrance
  • Phenotype*
  • Proteins / genetics


  • Bbs2 protein, human
  • Proteins
  • ARL6 protein, human
  • ADP-Ribosylation Factors

Supplementary concepts

  • Hereditary renal agenesis