ARL6 (OMIM: 608845), located at 3p12, encodes the ADP-ribosylation factor-like protein 6, a small GTPase that functions as a molecular switch. In its active, GTP-bound state, ARL6 recruits the BBSome complex to the primary cilium, which is required for trafficking membrane proteins essential for ciliary signaling and maintenance (PMID: 20603001, 20207729). Multiple independent reports have identified biallelic pathogenic variants in ARL6 in patients with classic Bardet-Biedl (BBS) features such as retinal dystrophy, obesity, polydactyly, renal anomalies, and cognitive involvement. Based on the ClinGen Lumping and Splitting Working Group criteria, this disease presents on a spectrum from syndromic Bardet-Biedl syndrome 3 (BBS3; MONDO:0010832) to non-syndromic retinitis pigmentosa 55 (RP55; MONDO:0013312); these were lumped and curated under “ciliopathy” (MONDO:0005308) because of a shared molecular mechanism and overlapping phenotypes. The mechanism is biallelic loss-of-function, resulting in disrupted ciliary transport and subsequent pleiotropic phenotypes.
The gene-disease relationship is supported by genetic evidence (12/12 points) from multiple independent cohorts, including nonsense, frameshift, missense, and large deletion variants (PMIDs: 15258860, 15314642, 32361989, 31736247, 27486776). Segregation evidence includes a LOD score of 9.85 in a large Bedouin kindred with a homozygous nonsense variant (p.Arg122Ter) (PMIDs: 7987310, 15258860). The relationship is also supported by experimental evidence (6/6 points). Functional studies demonstrate that pathogenic missense variants are unstable and degraded by the proteasome (PMID: 19236846), and that ARL6 modulates Wnt signaling (PMID: 20207729). A Bbs3-knockout mouse model recapitulates key BBS phenotypes including retinal degeneration and male infertility (PMID: 22139371). Furthermore, rescue experiments in zebrafish demonstrate that the systemic (BBS3) and eye-specific (BBS3L) isoforms have distinct functions that explain the syndromic versus non-syndromic presentations (PMID: 20333246).
In summary, there is definitive evidence supporting the relationship between ARL6 and autosomal recessive ciliopathies. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on July 14th, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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