PDE6D

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

The phosphodiesterase 6d (PDE6D) gene is located on chromosome 2 at 2q37.1 and encodes the retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, consisting of 150 amino acids. This protein is a key enzyme in the phototransduction cascade and also has an additional role in the PDE complex, in which the protein is thought to bind to prenyl groups of proteins to target them to subcellular organelles called cilia. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism and/or inheritance pattern and/or phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity: AR Ciliopathy: MONDO:0005308. *PDE6D* was first reported in relation to autosomal recessive Joubert syndrome 22 in 2014 (Thomas et al., PMID: 24166846). The mechanism of pathogenicity is known to be loss of function. Patients with *PDE6D* gene mutation present with the constellation of symptoms found in Joubert syndrome (JS): congenital cerebellar ataxia, congenital malformation of the brainstem, agenesis/hypoplasia of the cerebellar vermis leading to an abnormal respiratory pattern, nystagmus, hypotonia, ataxia, and delay in achieving motor milestones. Other features sometimes include retinal dystrophy, hepatopathy, nephronophthisis, and polydactyly. A total of 3 variants, (deletion, insertion and single nucleotide variant) have been reported in over 3 probands in over 5 publications from 2014 to 2023 (PMIDs: 24166846, 30293248, 30423442, 32055034 and 37644014). This gene-disease relationship is also supported by the following studies. Thomas et al.(PMID: 24166846) identified *PDE6D* as a novel disease gene in ciliopathies through comprehensive genetic, structural, and functional analyses. Using exome sequencing in a consanguineous family with Joubert syndrome–like features, they discovered a homozygous splice-site mutation in *PDE6D*, a gene encoding a prenyl-binding protein crucial for ciliary trafficking. Functional experiments in zebrafish demonstrated that loss of *PDE6D* leads to retinal and renal developmental defects that are rescued by wild-type but not mutant *PDE6D*, confirming the mutation’s pathogenicity. Structural modeling showed that the gene encodes key hydrophobic residues forming part of *PDE6D’s* nonpolar binding pocket; its deletion disrupts the protein’s conformation and ability to bind prenylated cargo. Proteomic analysis revealed that INPP5E, a farnesylated ciliary protein previously linked to JS, is a major *PDE6D* interactor. Mutant *PDE6D* fails to bind or deliver INPP5E to cilia and also loses interaction with ARL3, which mediates cargo release. Expression profiling found high *PDE6D* levels in the brain, kidney, and respiratory epithelia, which are tissues typically affected in ciliopathies. Overall, the article provides the first evidence that prenyl-binding–dependent trafficking defects underlie certain ciliopathies. A previous study in 2007 by Zhang et al. (PMID: 17496142) investigated the physiological role of *PDE6D* by generating a *PDE6D* knockout mouse. Despite being viable and fertile, knockout mice exhibited 20–30% lower body weight and progressive retinal dysfunction and degeneration. Immunoblotting and immunocytochemistry confirmed loss of *PDE6D* and reduced levels of prenylated phototransduction proteins such as GRK1 and cone PDE6α′, while non-prenylated proteins (rhodopsin, rod transducin) remained unaffected. GRK1 and cone *PDE6D* were mislocalized and largely absent from outer segments in both rods and cones, indicating defective trafficking of prenylated proteins. Functional testing showed increased single-photon sensitivity, delayed photoresponse recovery, and markedly reduced photopic b-wave amplitudes (−70%), consistent with impaired light adaptation. Histologically, the retina developed normally but displayed gradual rod/cone dystrophy, with outer segment shortening by 4 weeks and loss of photoreceptor nuclei by 20 months. Overall, the study demonstrated that *PDE6D* is essential for the proper transport of prenylated proteins to photoreceptor outer segments, and its absence leads to disrupted visual signaling and slowly progressive retinal degeneration. In summary, there is moderate evidence supporting the relationship between *PDE6D* and AR ciliopathy. This has been demonstrated in both clinical diagnostic and research settings. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date August, 27th, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0010176

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014297

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014297

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014297

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0014297

Submitter: G2P