Bardet-Biedl Syndrome (BBS) Panel

Bardet-Biedl Syndrome (BBS) is an autosomal recessive disorder marked by primary features of obesity, polydactyly, pigmentary retinopathy, hypogonadism, renal anomalies and cognitive impairment (Elbedour et al. 1994. PubMed ID: 7802002; Sheffield. 2010. PubMed ID: 20697559). Secondary features include diabetes, hypertension and congenital heart defects (Green et al. 1989. PubMed ID: 2779627). Although BBS is a rare condition, diagnosis is complicated by the fact that many of the clinical features (obesity, diabetes, hypertension, and developmental delay) are common. In addition, many of the BBS clinical features overlap with those of other well-described developmental disorders, including McKusick-Kaufman syndrome, Meckel-Gruber Syndrome, Joubert Syndrome , Nephronophthisis, Senior-Loken Syndrome, and Leber Congenital Amaurosis. Thus, molecular testing is often useful for confirmation of a clinical diagnosis and to aid in the treatment and management of BBS.

BBS is a genetically heterogeneous disorder known to be caused by pathogenic variants in at least 25 different genes including ARL6/BBS3, BBIP1/BBS18, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, CEP164, CEP290/BBS14, CFAP418/C8orf37, IFT27/BBS19, IFT74/BBS20, IFT172, LRRC45, LZTFL1/BBS17, MKKS/BBS6, MKS1/BBS13, NPHP1, SDCCAG8/BBS16, TMEM67, TRIM32/BBS11, TTC8/BBS8, TTC21B, and WDPCP/BBS15 (Forsythe and Beales 2015. PubMed ID: 20301537; Leitch et al. 2008. PubMed ID: 18327255; Kim et al. 2010. PubMed ID: 20671153; Otto et al. 2010. PubMed ID: 20835237; Lindstrand et al. 2016. PubMed ID: 27486776; Heon et al. 2016. PubMed ID: 27008867; Bujakowska et al. 2015. PubMed ID: 25168386; Lindstrand et al. 2014. PubMed ID: 24746959; Best et al. 2021. PubMed ID: 34716235). TMEM67 is included in this panel as it has been suggested to be a genetic modifier of the BBS phenotype (Leitch et al. 2008. PubMed ID: 18327255). BBS is marked by both intra- and inter-familial phenotypic variability.

It has been suggested that BBS has an oligogenic inheritance pattern. Triallelism hypothesis states that three pathogenic alleles in two genes are necessary for BBS. This hypothesis attempts to explain variable expressivity and the observation that several individuals with BBS have been found to have a third rare, possibly pathogenic variant in a second BBS gene (Katsanis et al. 2001. PubMed ID: 11567139; Katsanis. 2004. PubMed ID: 14976158; Leitch et al. 2008. PubMed ID: 18327255). However, others have not found evidence for triallelic inheritance patterns in their cohorts (Smaoui et al. 2006. PubMed ID: 16877420; Abu-Safieh et al. 2012. PubMed ID: 22353939). In the majority of reported cases two pathogenic variants in one gene are sufficient for BBS. However, the severity may be modulated by an additional hypomorphic or loss of function allele(s) at another locus. It is recommended to use an autosomal recessive inheritance model when counseling patients and their families (Forsythe and Beales 2015. PubMed ID: 20301537). See individual gene test descriptions for more information on molecular biology of gene products.

Clinical sensitivity for this BBS NGS test is ~80% (Forsythe and Beales. 2015. PubMed ID: 20301537; Lindstrand et al. 2016. PubMed ID: 27486776).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.5% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).