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.

Table 1: Overview of genes in Bardet Biedl panel

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ARL6 608845 Bardet-Biedl syndrome type 1; Bardet-Biedl syndrome 3; Retinitis pigmentosa 55 AR, DiR 7
BBIP1 613605 Bardet-Biedl syndrome 18 AR 1
BBS1 209901 Bardet-Biedl syndrome type 1 AR, DiR 14
BBS10 610148 Bardet-Biedl syndrome type 10 AR 12
BBS12 610683 Bardet-Biedl syndrome type 12 AR 8
BBS2 606151 Bardet-Biedl syndrome type 2; retinitis pigmentosa type 74 AR 16
BBS4 600374 Bardet-Biedl syndrome 4 AR 12
BBS5 603650 Bardet-Biedl syndrome 5 AR 27
BBS7 607590 Bardet-Biedl syndrome type 7 AR 17
BBS9 607968 Bardet-Biedl syndrome type 9 AR 23
CCDC28B 610162 Bardet-Biedl syndrome type 1 AR, DiR 1
CEP290 610142 Joubert syndrome type 5; Senior-Loken syndrome type 6; Meckel syndrome type 4; Leber congenital amaurosis type 10; Bardet-Biedl syndrome type 14 AR 52
IFT27 615870 Bardet-Biedl syndrome 19 AR 0
LZTFL1 606568 Bardet-Biedl syndrome 17 AR 6
MKKS 604896 McKusick-Kaufman syndrome; Bardet-Biedl syndrome type 6 AR 6
MKS1 609883 Meckel syndrome type 1; Bardet-Biedl syndrome type 13; Joubert syndrome type 28 AR 8
SDCCAG8 613524 Senior-Loken syndrome 7; Bardet-Biedl syndrome 16 AR 12
TMEM67 609884 COACH syndrome; Meckel Syndrome, Type 3; Joubert syndrome 6; nephronophthisis 11; Bardet-Biedl syndrome type 14 AR 18
TRIM32 602290 limb-girdle muscular dystrophy type 2H; Bardet-Biedl syndrome 11 AR 3
TTC8 608132 retinitis pigmentosa type 51; Bardet-Biedl syndrome type 8 AR 13
WDPCP 613580 Bardet-Biedl syndrome 15 AR 7