1. NGS panel - Genetic testing for Bardet-Biedl syndrome

Bardet Biedl

April 12, 2017

Clinical features

Bardet-Biedl Syndrome (BBS) is a rare, autosomal-recessive ciliopathy characterized by retinal dystrophy, obesity, renal abnormalities, genital abnormalities, postaxial polydactyly, and learning difficulties. To date, mutations in more than 20 different genes have been described as being responsible for BBS.

Primary clinical features of BBS include the following:

  • Rod-cone dystrophy, present in more than 90% of individuals1
  • Postaxial polydactyly involving either all four limbs (21% of cases)1 or the hands or feet alone
  • Truncal obesity, reported in 72-92% of affected individuals1
  • Learning disabilities and cognitive impairment
  • Hypogonadism (in males) or genital abnormalities (in females)2
  • Abnormal renal function leading to end-stage renal disease can be a major cause of morbidity and is present in 53-82% of affected individuals3, 1.

Secondary clinical features of BBS include the following:

  • Speech delay/disorder
  • Developmental delay
  • Behavioral abnormalities (described in about 33% of individuals with BBS4
  • Eye abnormalities include strabismus, cataracts, and astigmatism
  • Brachydactyly/syndactyly.
  • Ataxia/poor coordination/imbalance and mild hypertonia
  • Diabetes mellitus
  • Orodental abnormalities include dental crowding, hypodontia, small dental roots, and high-arched palate
  • Cardiovascular anomalies were reported in 7-50% 5
  • Hepatic involvement, including perilobular fibrosis, periportal fibrosis with small bile ducts, biliary cirrhosis, portal hypertension, and congenital cystic dilations.
  • Craniofacial defects in BBS include macrocephaly, brachycephaly, narrow forehead, narrow palpebral fissures, depressed nasal bridge and others.

Pathogenic variants in more than 20 genes are known to be associated with BBS. CENTOGENE offers a 21-gene panel with the most common genetic variants associated with BBS (see Table 1).

Overview of the genes in CENTOGENE´s Bardet Biedl panel

Locus Name Gene OMIM Chromosome Locus Protein Frequency of mutations (%)
BBS3 ARL6 608845 3q11.2 ADP-ribosylation factor-like protein 6 Rare11
BBS18 BBIP1 613605 10q25.2 BBSome-interacting protein 1 Rare11
BBS1 BBS1 209901 11q13.2 Bardet-Biedl syndrome 1 protein ~23.2%6
BBS10 BBS10 610148 12q21.2 Bardet-Biedl syndrome 10 protein ~20% 7
BBS12 BBS12 610863 4q27 Bardet-Biedl syndrome 12 protein ~5% 9
BBS2 BBS2 606151 16q13 Bardet-Biedl syndrome 2 protein ~8.1% 6
BBS4 BBS4 600374 15q24.1 Bardet-Biedl syndrome 4 protein 2.3%11
BBS5 BBS5 603650 2q31.1 Bardet-Biedl syndrome 5 protein Rare11
BBS7 BBS7 607590 4q27 Bardet-Biedl syndrome 7 protein ~1.5% 6
BBS9 BBS9 607968 7p14.3 Protein PTHB1 C~6.0% 8
BBS1 CCDC28B 610162 1p35.2 Coiled-coil domain containing protein 28B Rare11
BBS14 CEP290 610142 12q21.32 Centrosomal protein of 290 kDa Rare11
BBS19 IFT27 615870 22q12.3 Intraflagellar transport protein 27 homolog Rare11
BBS17 LZTFL1 606568 3p21.31 Leucine zipper transcription factor-like protein 1 Rare11
BBS6 MKKS 604896 20p12.2 McKusick-Kaufman/BBS putative chaperonin ~5.8% 6
BBS13 MKS1 609883 17q22 Meckel syndrome type 1 protein ~4.5% 10
BBS16 SDCCAG8 613524 1q43-q44 Serologically defined colon cancer antigen 8 Rare11
BBS14 TMEM67 609884 8q22.1 Transmembrane protein 67 Rare11
BBS11 TRIM32 602290 9q33.1 E3 ubiquitin-protein ligase TRIM32 Rare11
BBS8 TTC8 608132 14q31.3 Tetratricopeptide repeat protein 8 ~1.2% 6
BBS15 WDPCP 613580 2p15 WD repeat-containing and planar cell polarity effector protein fritz homolog Rare11

There is currently no cure for Bardet-Biedl syndrome. Current treatment plans for Bardet-Biedl syndrome address its individual symptoms. Due to the progressive vision loss, visual aids and educational programs specific to people with visual impairments are recommended. Furthermore, medications are used for the regulation of hypertension and diabetes mellitus, and diet and exercise are recommended for obesity.

CENTOGENE offers full gene sequencing of Bardet Biedl panel (genes: ARL6, BBIP1, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, CCDC28B, CEP290, IFT27, LZTFL1, MKKS, MKS1, SDCCAG8, TMEM67, TRIM32, TTC8, WDPCP).

Differential diagnosis

The differential diagnosis of Bardet Biedl syndrome disorders – depending on the major symptoms in the initial case – includes the following diseases1:

  • McKusick-Kaufman syndrome
  • Alström syndrome
  • Joubert syndrome
  • Senior-Løken syndrome (SLS)
  • Leber congenital amaurosis (LCA)
  • Biemond syndrome II

Testing strategy

CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Bardet Biedl using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Bardet Biedl panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Bardet Biedl panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.

Referral reasons

The following individuals are candidates for this particular gene testing

  • Individuals with a family history of disease and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling this disease
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.

Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s Bardet Biedl panel can be found in our genetic test catalogue.