Inheritance

Autosomal recessive

Prevalence

 1 in 140,000 to 1 in 160,000 newborns

Source:Bardet-Biedl syndrome: MedlinePlus Genetics

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

OMIM: AR Bardet-Biedl syndrome, AR retinitis pigmentosa. ClinGen - dosage sensitivity HI score 30 (associated w/ AR phenotype). GenCC - strong for Bardet Biedl (Ambry, Invitae) and retinitis pigmentosa (invitae).

Clinical Validity Scoring Notes and points

• c.364C>T p.R122* - rare in gnomAD at 0.0002% (7/1111456) European non-Finnish chr, NMD+. PMID: 15258860 - Variant homozygous in the BBS3-linked kindred; while they only show a small part of the family in fig 3, in the text they state that the variant segregated in all 13 affected family members, unaffected parents were all het, and unaffected sibs were het or wt/wt. 2 VARIANT POINTS, 3 SEGREGATION POINTS

• c.480-1700_535+2392del4148 p.(Cys160*) - absent gnomAD, NMD+. PMID: 19858128 - variant found homozygous in family KFSH-F004, results in the skipping of exon 8 per fig 2 and causes a nonsense. Based on the methods, they collected blood from all affected family members, and family segregation was checked whenever possible. Unclear if segregation performed. 2 VARIANT POINTS

• Deletion of exons 1-3 - PMID: 19858128 - Per table 3, variant homozygous in patient with Bardet-Biedl syndrome 2 variant points NMD+

Clinical Validity Points Total

At least 9 (Stopped when I got enough evidence for moderate w/ LOF mechanism)

Source: PMID: 15258860, 19858128, 19858128

Clinical Validity Classification

At least Moderate

Molecular Mechanism

Loss of function

Source: PMID: 15258860, 19858128, 19858128

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Retinal cone-rod dystrophy

Central obesity

Postaxial polydactyly

Cognitive impairment

Hypogonadism & genitourinary abnormalities

Kidney disease

Other features

Sources: PMID : 20301537

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

Curation Summary

The ARL6 gene is associated with autosomal recessive Bardet-Biedl syndrome, which is characterized by retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, hypogonadism & genitourinary abnormalities, kidney disease, and additional features (PMID : 20301537). Variants in ARL6 have also been reported in autosomal recessive retinitis pigmentosa (MIM: 613575).

Case ID, Curator name, Date, Jira ticket link