Bardet-Biedl Syndrome-Multiple Kaleidoscope Images: Insight into Mechanisms of Genotype-Phenotype Correlations

Abstract

Bardet-Biedl Syndrome is a rare non-motile primary ciliopathy with multisystem involvement and autosomal recessive inheritance. The clinical picture is extremely polymorphic. The main clinical features are retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, hypogonadism and genitourinary abnormalities, and kidney disease. It is caused by various types of mutations, mainly in genes encoding BBSome proteins, chaperonins, and IFT complex. Variable expressivity and pleiotropy are correlated with the existence of multiple genes and variants modifiers. This review is focused on the phenomena of heterogeneity (locus, allelic, mutational, and clinical) in Bardet-Biedl Syndrome, its mechanisms, and importance in early diagnosis and proper management.

Keywords: Bardet–Biedl Syndrome; ciliopathy; heterogeneity; pleiotropy; variable expressivity.

Figure 1

Heterogeneity in Bardet Biedl Syndrome-determinants and clinical effects. Created with BioRender.com (accessed on 15 August 2021).

Figure 2

Pathogenic variants in BBSome [34]. BBS1: Bardet-Biedl syndrome 1; BBS2: Bardet-Biedl syndrome 2; BBS4: Bardet-Biedl syndrome 4; BBS5: Bardet-Biedl syndrome 5; BBS7: Bardet-Biedl syndrome 7; TTC8: tetratricopeptide repeat domain 8; BBS9: Bardet-Biedl syndrome 9; BBIP1: BBSome interacting protein 1.

Figure 3

Pathogenic variants in other genes of BBS [34]. ARL6: ADP ribosylation factor like GTPase 6; MKKS: MKKS centrosomal shuttling protein; BBS10: Bardet-Biedl syndrome 10; TRIM32: tripartite motif containing 32; BBS12: Bardet-Biedl syndrome 12; MKS1: MKS transition zone complex subunit 1; CEP290: centrosomal protein 290; WDPCP: WD repeat containing planar cell polarity effector; SDCCAG8: SHH signaling and ciliogenesis regulator SDCCAG8; LZTFL1: leucine zipper transcription factor like 1; IFT27: intraflagellar transport 27; IFT74: intraflagellar transport 74; C8orf37: chromosome 8 open reading frame 37; SCLT1: sodium channel and clathrin linker 1; NPHP1: nephrocystin 1; SCAPER: S-phase cyclin A associated protein in the ER.