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

Bardet Biedl

March 29, 2018

Disease summary

Bardet-Biedl syndrome (BBS) is a rare, autosomal-recessive ciliopathy characterized by retinal dystrophy, obesity, renal abnormalities, and genital abnormalities, postaxial polydactyly and learning difficulties. To date, mutations in more than 20 different genes have been described as being responsible for BBS (ARL6, BBIP1, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, CCDC28B, CEP290, IFT27, LZTFL1, MKKS, MKS1, SDCCAG8, TMEM67, TRIM32, TTC8, WDPCP) 1, 11.

Bardet-Biedl syndrome (BBS) infographics

Autosomal recessive, digenic recessive inheritance

1/100,000-160,000 (Northern European and North American populations); 1/13,500 (Arab populations) 1, 2, 11.

Primary clinical features for Bardet-Biedl syndrome include the following:

  • Rod-cone dystrophy, (>90% of cases)1
  • Postaxial polydactyly (21% of cases)1
  • Truncal obesity(72-92% of cases)1
  • Learning disabilities and cognitive impairment.
  • Hypogonadism (males) or genital abnormalities (in females)2
  • Renal anomalies (53-82% of cases) 3, 1, 11.                                                              

Secondary clinical features of Bardet-Biedl syndrome include the following1, 11:

  • Speech delay/disorder
  • Developmental delay
  • Behavioral abnormalities
  • Eye abnormalities (strabismus, cataracts, and astigmatism)
  • Brachydactyly/syndactyly
  • Ataxia/poor coordination/imbalance and mild hypertonia
  • Diabetes mellitus
  • Orodental abnormalities (dental crowding, hypodontia, small dental roots, and high-arched palate)
  • Cardiovascular anomalies5.
  • Hepatic involvement
  • Hirschsprung disease
  • Anosmia
  • The diagnosis of Bardet-Biedl syndrome relies on clinical findings and family history.
  • Suggested criteria is the presence of:

            o    4 primary features or

            o    3 primary features + 2 secondary features

  • Diagnosis is confirmed by the identification of a pathogenic variant in one of the following genes: ARL6, BBIP1, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, CCDC28B, CEP290, IFT27, LZTFL1, MKKS, MKS1, SDCCAG8, TMEM67, TRIM32, TTC8, WDPCP.

There is no cure for Bardet-Biedl syndrome to date, but treatment can relieve symptoms 11.

  • Visual aids and educational programs for the visually impaired.
  • Obesity is managed with diet, exercise, and behavioral therapies.
  • Speech therapy for speech delay/impairment.
  • Renal anomalies and hypertension are treated as in the general population.
  • Hydrocolpos, vaginal atresia, or hypospadias may be surgically corrected.
  • Hormone replacement therapy for hypogonadism.
  • Cardiac abnormalities are treated as in the general population. 
  • McKusick-Kaufman syndrome
  • Alström syndrome
  • Joubert syndrome
  • Senior-Løken syndrome (SLS)
  • Leber congenital amaurosis (LCA)
  • Biemond syndrome II
  • Chronic pancreatitis

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Bardet-Biedl syndrome using NGS Panel Genomic:

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

Step 2: If no pathogenic variant is identified in Step1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.   

  • Individuals with a positive family history of Bardet-Biedl syndrome.
  • Individuals with most common symptoms of Bardet-Biedl syndrome (regardless of family history).

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

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