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ARL6 Gene Curation

ARL6 Gene Curation

Owned by Andrea Oza
2023-12-08
3 min read

Gene-disease assertions not curated here (add link or write note): AR retinitis pigmentosa (may be in the spectrum of BBS)

Disease

Bardet-Biedl syndrome

 

Disease

Bardet-Biedl syndrome

 

Inheritance

Autosomal recessive

 

Prevalence

Orphanet

Medline Plus Genetics

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

Source:Bardet-Biedl syndrome: MedlinePlus Genetics

 

Rapid or full curation?

Rapid
Full

 

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

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

At least Moderate

 

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function

Source: PMID: 15258860, 19858128, 19858128

 

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Source:

 

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

 

 

Severity

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

 

 

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 @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

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

 

 

 

 

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