Neurological ciliopathies
Gene: ARL3Comment on list classification: New gene submitted by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype (possible - RP, and probable - Joubert syndrome).
As there are only 2 cases that have been associated with Joubert syndrome (PMID:30269812) and the knockout mouse model does not appear to have a neurological phenotype (PMID:16565502) this gene has been given an Amber rating until further evidence is available.Created: 18 Oct 2021, 10:32 a.m. | Last Modified: 18 Oct 2021, 10:32 a.m.
Panel Version: 1.20
Comment on publications: PMID:30269812 describes 2 unrelated consanguineous families (Saudi and Pakistani). Both have phenotype resembling Joubert syndrome (night blindness, rod-cone dystrophy, mild dysmorphic features, hypotonia (only in 1 family), ataxia, cerebellar vernis hypoplasia). Both are homozygous missense for the same amino acid residue (R149C, R149H). The authors performed some in vitro functional analysis.
PMID:16565502 describes a knockout mouse model of Arl3. The homozygous knockouts developed ciliary disease affecting kidney, biliary tract, pancreas and retina. However, there was no mention of a brain phenotype.
PMID:31743939 describes 2 large consanguineous Pakastani families with the same homozygous variant (Arg99Ile). There are 8 affected individuals in total and 7/8 had cone-rod dystrophy and no features of Joubert syndrome.
PMID:33748123 describes a Chinese family. Proband is compound het (c.91A>G, p.T31A; c.353G>T, p.C118F) and has retinal dystrophy. Heterozygous father has late onset and mild rode-cone dystrophy. Mother and sister (het) are normal. All family members did not have any other phenotypes.
PMID:26964041 describes a family with affected mother, son and daughter with retinitis pigmentosa. Affected patients were heterozygosity for Y90C. The mother's parents do not have the variant suggesting that it is a de novo event in the mother. No functional studies of the variant were performed.
PMID:30932721 reports a case where a patient has a de novo Y90C variant and has RP.
PMID:34485303 reports a heterozygous Asp67Val variant segregating in an Ashkenazi Jewish family with a dominant inherited retinal degenerations.Created: 18 Oct 2021, 10:29 a.m. | Last Modified: 18 Oct 2021, 10:29 a.m.
Panel Version: 1.19
4 individuals from 2 unrelated consanguineous families with a phenotype resembling Joubert syndrome with homozygous missense mutations affecting the same residue (R149C, R149H), and supporting in vitro functional assays. An Arl3 null mouse model has a ciliary disease phenotype affecting the kidney, biliary tract, pancreas, and retina.
Sources: Expert listCreated: 25 May 2020, 2:24 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Joubert syndrome 35 MIM#61816
Publications
Variants in this GENE are reported as part of current diagnostic practice
Gene: arl3 has been classified as Amber List (Moderate Evidence).
Tag watchlist tag was added to gene: ARL3.
Publications for gene: ARL3 were set to 30269812; 16565502
Phenotypes for gene: ARL3 were changed from Joubert syndrome 35 MIM#61816 to Joubert syndrome 35, OMIM:61816
gene: ARL3 was added gene: ARL3 was added to Neurological ciliopathies. Sources: Expert list Mode of inheritance for gene: ARL3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARL3 were set to 30269812; 16565502 Phenotypes for gene: ARL3 were set to Joubert syndrome 35 MIM#61816 Review for gene: ARL3 was set to GREEN gene: ARL3 was marked as current diagnostic