GUCY2D

Inheritance Pattern: AD

Disease ID:MONDO:0100441

Submitter: ClinGen

The *GUCY2D* gene was first reported in relation to autosomal dominant cases of cone-rod dystrophy 6 (MONDO: 0011143) in 1998 (Kelsell et al., PMID: 9618177, Perrault et al. PMID: 9683616). Affected individuals have since been identified in a number of other publications (PMID: 10676808, PMID: 26298565, PMID: 25515582), with causal monoallelic variants in *GUCY2D*. Patients typically present with pediatric onset of progressively reduced visual acuity, myopia, photophobia, color vision defects, abnormalities of retinal pigmentation, and Bull’s eye maculopathy. Electroretinogram readings indicate loss of cone responses and less severe loss of rod responses. Macular optical coherence tomography generally indicates reduced thickness of the retinal photoreceptor layers, which is accompanied by loss of cone cell density. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, these cases were compared with other diagnoses reported in association with *GUCY2D* variants. For example, cases from a large Northern Irish family linked to a monoallelic variant in *GUCY2D* have been diagnosed with central areolar choroidal dystrophy 1 (PMID: 22695961). While the associated variant is located outside of the dimerization domain, the shared mode of inheritance and phenotypic overlap led this disease entity to be combined with autosomal dominant cases of cone-rod dystrophy 6 into a single gene curation, with the lumped disease entity referred to as GUCY2D-related dominant retinopathy (MONDO:0100441). On the other hand, cases with overlapping phenotypes harboring biallelic *GUCY2D* variants have been diagnosed with autosomal recessive cone-rod dystrophy 6, Leber congenital amaurosis 1, or congenital stationary night blindness type 1I (PMID: 20517349). These cases differ in both their mode of inheritance and molecular mechanism (biallelic loss of function in the GUCY2D gene product). Therefore, recessive cases have been lumped into a separate disease entity, referred to as GUCY2D-related recessive retinopathy (MONDO: 0100453). Nine suspected pathogenic variants have been scored as part of this curation (six missense variants disrupting codon 838, two additional missense variants disrupting the coiled-coil dimerization domain, and one variant in the C-terminal catalytic domain), which have been collectively reported in ten probands in six publications (PMID: 9618177, PMID: 9683616, PMID: 10676808, PMID: 26298565, PMID: 25515582, PMID: 22695961). All ten probands are heterozygous for their respective variants. One family with segregation evidence has contributed to the scoring of the gene-disease relationship (PMID: 9618177). More case-level data and families with segregation data are available in the above publications, but have not been scored as part of this curation as the maximum scoring for this evidence type has already been reached. The mechanism of pathogenicity appears to be monoallelic *GUCY2D* dysfunction, characterized in most cases by missense variants in the region of *GUCY2D* encoding the dimerization-mediating coiled-coil domain. Nine out of ten probands found for this curation harbor a heterozygous variant allele within this region of *GUCY2D*. These substitutions are predicted to enhance the affinity of GUCY2D protein for its guanylate cyclase-activating protein GCAP-1 (GUCA1A), conferring the ability for the variant proteins to be enzymatically stimulated by GCAP-1 at higher concentrations of calcium ions than the wild-type protein (PMID: 10430891, PMID: 30319355). One of the autosomal dominant cases included in this curation harbors a heterozygous variant located outside of the dimerization-mediating domain, and will require additional functional study to confirm its mechanism of pathogenicity (PMID: 22695961). This gene-disease association is supported by experimental evidence that *GUCY2D* expression is dramatically higher in the retina relative to control tissues (PMID: 30239781), particularly along the retinal outer nuclear layer (PMID: 1356371). Biochemical studies have demonstrated that *GUCY2D* encodes a receptor guanylyl cyclase that catalyzes cGMP production as part of the recovery of the dark state following visual excitation (PMID: 1356371). The enzymatic activity of GUCY2D protein is stimulated by the GCAP1 protein encoded by the *GUCA1A* gene, which harbors variants causal for autosomal dominant cone-rod dystrophy 3 (PMID: 10430891). Transgenic zebrafish (PMID: 23328348) and mouse models (PMID: 27703005) expressing a variant observed in affected human patients recapitulate features of the disease entity, including the mode of inheritance, electroretinogram abnormalities, retinal outer nuclear layer thinning, and photoreceptor cell loss. In summary, *GUCY2D* is definitively associated with GUCY2D-related dominant retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification. This classification was approved by the ClinGen Retinal GCEP on May 27, 2022 (SOP Version 8).

Inheritance Pattern: AR

Disease ID:MONDO:0032811

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0008764

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0008764

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0008982

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0100453

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0100441

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0008982

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0008764

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0011143

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0100453

Submitter: ClinGen

The *GUCY2D* gene was first reported in relation to autosomal recessive cases of Leber congenital amaurosis in 1996 (Perrault et al., PMID: 8944027). Affected individuals have since been identified in a number of other publications (PMID: 16505055, PMID: 29559409, PMID: 23035049), with causal biallelic variants in *GUCY2D* specifically diagnostic for either Leber congenital amaurosis 1 (more severe) or congenital stationary night blindness type 1I (milder and later onset). Both disease entities are completely penetrant, however, patients diagnosed with Leber congenital amaurosis 1 present with severe visual impairment before the age of 5 (usually during the first year of life) while their counterparts with congenital stationary night blindness type 1I are diagnosed between the ages of 9 and 45, presenting with night blindness since childhood and gradual progression to mild retinal dystrophy (PMID: 29559409). Patients with Leber congenital amaurosis 1 also exhibit other eye-specific features, including nystagmus, photophobia, strabismus, eye poking, keratoconus, attenuation of retinal blood vessels, optic disc pallor, and mild retinal pigment epithelium mottling, often with a relatively normal appearance to the fundus. Patients with congenital stationary night blindness type 1I exhibit only a subset of these features, including attenuation of retinal blood vessels and progressive visual field constriction. Electroretinogram (ERG) response is nondetectable in Leber congenital amaurosis 1 patients, however, those with congenital stationary night blindness type 1I initially exhibit nondetectable responses only in rod-based ERG, while cone-based ERG responses may remain normal until the third decade of life or later. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the molecular mechanism (biallelic loss of function in the GUCY2D gene product) and mode of inheritance (autosomal recessive) to be consistent among unrelated patients diagnosed with either Leber congenital amaurosis 1 or congenital stationary night blindness type 1I, while the phenotypic variability between them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, cases of Leber congenital amaurosis 1 or congenital stationary night blindness type 1I have been lumped into a single disease entity, referred to as *GUCY2D*-related recessive retinopathy (MONDO:0100453). Two additional disease entities, cone-rod dystrophy 6 and central areolar choroidal dystrophy 1, were asserted in relation to monoallelic variants in *GUCY2D*, particularly those located in the dimerization domain (PMID: 11115851, PMID: 11709018, PMID: 29061346). While these disease entities are characterized by similar phenotypes, their different mode of inheritance and unique variants suggested a different mechanism of pathogenesis. Thus, *GUCY2D* was separately curated for its relationship to this disease entity, referred to as *GUCY2D*-related dominant retinopathy (MONDO:0100441). Eight suspected pathogenic variants were scored as part of this curation (two nonsense, one frameshift, and five missense), which have been collectively reported in twelve probands in three publications (PMID: 8944027, PMID: 16505055, PMID: 29559409). Eight probands were homozygous for their respective variants (PMID: 8944027, PMID: 16505055), and five were reported to have consanguineous parents (PMID: 8944027, PMID: 16505055). The four other probands were compound heterozygotes within the *GUCY2D* locus (PMID: 16505055, PMID: 29559409). Two families with segregation evidence were available in these publications (PMID: 8944027), and contributed to the scoring of the gene-disease relationship. More case-level data was available (PMID: 23035049, PMID: 29559409), but was not scored as part of this curation as the maximum scoring for this evidence type had already been reached. This gene-disease relationship has not been studied in case-control studies at the single variant level or aggregate variant level. The mechanism of pathogenicity appears to be biallelic loss of function, characterized in some cases by frameshift or nonsense variants predicted to trigger a decrease in the amount of the gene product (PMID: 8944027, PMID: 29559409). All probands found for this curation harbored two variant alleles within the *GUCY2D* locus. This gene-disease association is also supported by experimental evidence that *GUCY2D* expression is dramatically higher in the retina relative to control tissues (PMID: 30239781), particularly along the retinal outer nuclear layer (PMID: 1356371). Proper subcellular localization of GUCY2D protein requires its C-terminus to physically interact with the RD3 protein, which is encoded by a gene that harbors causal variants for Leber congenital amaurosis 12 (PMID: 21078983). Biochemical studies have demonstrated that *GUCY2D* encodes a receptor guanylyl cyclase that catalyzes cGMP production as part of the recovery of the dark state following visual excitation (PMID: 1356371). This helps explain why chickens homozygous for a null variant of the *GUCY2D* ortholog exhibit dramatically reduced cGMP levels within the retina, nondetectable ERG responses from rod and cone photoreceptors, early onset blindness, and optokinetic reflex abnormalities analogous to nystagmus (PMID: 9448321). Similarly, mice with homozygous knockout of *Gucy2e* (the murine *GUCY2D* ortholog) exhibit degeneration and loss of cone photoreceptor cells in the outer nuclear layer, nondetectable cone-based ERG responses, reduced amplitude of rod-based ERG responses, and loss of visual acuity (PMID: 10407028, PMID: 17255100, PMID: 21671801). Rod photoreceptor function has been shown to be relatively preserved in these mice due to their dependence on a gene paralog (PMID: 17255100). These mouse phenotypes can be partially rescued by injection of adeno-associated virus (AAV) delivering wild-type human *GUCY2D* or mouse *Gucy2e*. In summary, *GUCY2D* is definitively associated with *GUCY2D*-related recessive retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification.

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet