PMID: 30667376

ExperimentName: The Cpfl1 mouse harbors loss-of-function variants in the Pde6c gene.

NonHumanModel: Mus musculus

GeneAlteration: The model animals are homozygous for two different loss-of-function variants predicted to introduce premature stop codons into the Pde6c locus. One is a 116-bp insertion between exons 4 and 5, while the other is a 1-bp deletion in exon 7.

ModelPhenotype: HP:0008020 (cone dystrophy), HP:0030465 (Undetectable light-adapted electroretinogram), normal dark-adapted ERG, rapid and progressive loss of cone photoreceptors from the photoreceptor layer

HumanPhenotype: HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030534 (Abnormal best corrected visual acuity test), HP:0000551 (Color vision defect), HP:0000613 (Photophobia), HP:0000639 (Nystagmus), HP:0007401 (Macular atrophy), HP:0000545 (Myopia)

ModelEvidence: This is a naturally occurring mouse model with lack of light-adapted ERG responses and normal dark-adapted ERG responses (Figure 1). The mice also exhibit rapid and progressive loss of cone photoreceptors from retinal sections (Figure 2).

ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied naturally occurring variants disrupting the Pde6c locus.

Case#: Chang_2009_Family_CHRO287_Proband_II:1, male, age and family origin not described

CasePresentingHPOs: HP:0011516 (Achromatopsia)

CaseHPOFreeText: The proband was previously diagnosed with achromatopsia.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his parents were initially subjected to genotyping of the CNGA3, GNGB3, and GNAT2 loci, confirming absence of causal variants in these known achromatopsia-related genes.

CaseMethod1: Sanger sequencing of CNGA3, GNGB3, and GNAT2

CaseMethod2: Sanger sequencing of the 22 exons and flanking regions of PDE6C

CaseGenotypingMethod: CNGA3, GNGB3, and GNAT2 were previously screened / known not to harbor causal variants for achromatopsia. The family members were then subjected to Sanger sequencing of the 22 exons and flanking regions of PDE6C.

Variant: The proband harbors the NM_006204.4(PDE6C):c.826C>T (p.Arg276Ter) and NM_006204.4(PDE6C):c.2457T>A (p.Tyr819Ter) variants in the compound heterozygous state.

ClinVar ID: 8773, 8774

gnomAD: The NM_006204.4(PDE6C):c.826C>T (p.Arg276Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00006152 (1 allele / 16256 total alleles) in the African / African-American population, with 0 homozygotes. The NM_006204.4(PDE6C):c.2457T>A (p.Tyr819Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_006204.4(PDE6C):c.826C>T (p.Arg276Ter) is a nonsense variant in exon 4 of 22 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 68% of the protein product. NM_006204.4(PDE6C):c.2457T>A (p.Tyr819Ter) is a nonsense variant in exon 21 of 22 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 5% of the protein product.

CaseAddInfo: The patient has an affected brother who shares the same compound heterozygous genotype, while the parents and one other sibling are each unaffected carriers.

CasePMIDs: N/A

Case#: Chang_2009_Family_CHRO572_Proband_II:1, male, age and family origin not described

CasePresentingHPOs: HP:0011516 (Achromatopsia)

CaseHPOFreeText: The proband was previously diagnosed with achromatopsia.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: The proband and his family members were initially subjected to genotyping of the CNGA3, GNGB3, and GNAT2 loci, confirming absence of causal variants in these known achromatopsia-related genes.

CaseMethod1: Sanger sequencing of CNGA3, GNGB3, and GNAT2

CaseMethod2: Sanger sequencing of the 22 exons and flanking regions of PDE6C

CaseGenotypingMethod: CNGA3, GNGB3, and GNAT2 were previously screened / known not to harbor causal variants for achromatopsia. The family members were then subjected to Sanger sequencing of the 22 exons and flanking regions of PDE6C.

Variant: The proband harbors the NM_006204.4(PDE6C):c.1682dup (p.Tyr561Ter) variant in the homozygous state.

ClinVar ID: 8775

gnomAD: The NM_006204.4(PDE6C):c.1682dup (p.Tyr561Ter) variant was not found in gnomAD v2.1.1.

VariantEvidence: NM_006204.4(PDE6C):c.1682dup (p.Tyr561Ter) is a nonsense variant in exon 13 of 22 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 35% of the protein product.

CaseAddInfo: The patient's parents and sister are each unaffected heterozygous carriers of the variant.

CasePMIDs: N/A

PMID: 18824093

Gene: PDE6C

HGNC: 8787

Disease: cone dystrophy 4

MONDO: 0013129

InheritancePattern: recessive

Prevalence: cone dystrophy in general is estimated to have a prevalence of 1 in 40,000 (PMID: 30578485).

Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.