Case#: Patient 5, male, 16 years (at report)

CaseHPOs: HP:0000613, HP:0007663, HP:0000551 (photophobia, reduced visual acuity, color vision defect)

CaseHPOsFreeText: Poor vision and photophobia since the age of 4. BCVA was 0.4 LogMAR in right eye and 0.52 LogMAR in left eye with a refractive error of −5.75 sph −3.00 cyl/15° D in right eye and of −6.00 sph −3.50 cyl/170° D in left eye. Fundus exam showed normal optic disk, a loss of the foveal reflex, and peripheral RPE mottling. Fundus autofluorescence revealed a central hypofluorescence with a mild perifoveal hyperfluorescent area in both eyes while OCT imaging showed a foveal photoreceptor disruption associated with a normal central macular thickness and relative sparing of paracentral retina (Figure 6). Flash full-field ERG recordings showed reduced responses mostly for the photopic component. Visual fields display a central scotoma.

CaseNotHPOs:

CasePreviousTesting: None mentioned but note that, in this study, DNA from all patients was analyzed by CORD NGS panel.

CaseMethod1: NGS panel

CaseGenotypingMethod: CORD NGS panel - ABCA4, ADAM9, AIPL1, C8orf37, CFAP410 (C21orf2), CACNA1F, CACNA2D4, CDHR1, CEP78, CNGA3, CRX, DRAM2, GUCA1A, GUCY2D, UNC119, IFT81, KCNV2, PDE6C, PITPNM3, POC1B, PROM1, PRPH2, RAB28, RAX2, RIMS1, RPGR, RPGRIP1, SEMA4A, TTLL5.

Variant: Variant 1) c.409C>T (p.Arg137Ter)(paternal) Variant 2) c.77C>A (p.Thr26Asn)(maternal)

ClinVar: Variant 1) 60755; Variant 2) N/A

CAID: Variant 1) CA144657; Variant 2) CA356375011

gnomAD: Variant 1) 0.00001764 (European non-Finnish). No homozygotes in any population. Variant 2) Not in gnomAD

VariantEvidence: Variant 1) no nonsense-mediated decay of mRNA was previously reported (Roosing et al, 2013). In the current paper, structural analysis showed that truncation would delete the α4, β6, and α5 structural elements. The lack of β6 and α5 would most likely prevent the correct α/β fold from forming, affecting the guanine nucleotide binding pocket, and resulting in protein degradation. Variant 2) Molecular dynamics simulations of p.Thr26Asn in both its active and inactive states revealed an allosteric structural mechanism that impairs the binding of Mg2+, thus decreasing the affinity for GTP. The impaired GTP-GDP exchange ultimately locks Rab-28 in a GDP-bound inactive state.

CaseAddInfo: Parents and brother are clinically unaffected. The father and brother are heterozygous for the nonsense variant and the mother is heterozygous for the missense variant.

Case#: Patient 4, 64 years (at report), female

CaseHPOs: HP:0000613, HP:0007663, HP:0000551 (photophobia, reduced visual acuity, color vision defect)

CaseHPOsFreeText: Relatively late onset of disease (first symptoms around age 30 years). 1.7 LogMAR in both eyes. Refractive error was −2.00 sph in both eyes. Fundus exam showed a tigroid aspect with vessel thinning, macular atrophy, and optic pallor. Flash full-field ERG recordings showed a non-detectable response for the photopic component and a reduced response for the scotopic response. MfERG response was markedly reduced but still detectable in both eyes, presenting a residual foveal cone function. OCT macular scan showed a marked foveal thinning with advanced photo-receptor layer disruption (Fig 5)

CaseNotHPOs:

CasePreviousTesting: None mentioned but note that, in this study, DNA from all patients was analyzed by CORD NGS panel.

CaseMethod1: NGS panel

CaseGenotypingMethod: CORD NGS panel - ABCA4, ADAM9, AIPL1, C8orf37, CFAP410 (C21orf2), CACNA1F, CACNA2D4, CDHR1, CEP78, CNGA3, CRX, DRAM2, GUCA1A, GUCY2D, UNC119, IFT81, KCNV2, PDE6C, PITPNM3, POC1B, PROM1, PRPH2, RAB28, RAX2, RIMS1, RPGR, RPGRIP1, SEMA4A, TTLL5.

Variant: c.321G>A (p.Trp107Ter), homozygous

ClinVar: N/A

CAID: CA356373812

gnomAD: The variant is absent in gnomAD.

VariantEvidence: Structural analysis of p.Trp107Ter suggested that truncation of the protein sequence after residue W107 would break up helix α3, resulting in the absence of the C-terminal part of α3, β5, α4, β6, and α5. Missing structural elements β5, β6, and α5 would most probably result in failure to fold correctly or bind GTP/GDP causing degradation.

Case#: Patient 2, male, 33 (at report), 6 years old at onset

CaseHPOs: HP:0000613, HP:0007663, HP:0000551 (photophobia, reduced visual acuity, color vision defect)

CaseHPOsFreeText: BCVA LogMAR 1 for both eyes, refractive error −4.25 sph −2.00 cyl/180° D in right eye and −4.00 sph −2.50 cyl/30° D in left eye. The fundus exam showed normal optic disk, signs of foveal atrophy, and “salt and pepper” peripheral retinopathy. Fundus autofluorescence revealed a dark central area due to the absence of the RPE surrounded by an unusual hyperfluorescent perifoveal ring in both eyes while infrared retinography showed foveal atrophy. OCT imaging revealed a marked reduction of the foveal thickness associated with a photoreceptor layer disruption (Figure 3). Goldmann visual field test showed central scotoma with a mild peripheral constriction.

CaseNotHPOs:

CasePreviousTesting: None mentioned but note that, in this study, DNA from all patients was analyzed by CORD NGS panel.

CaseMethod1: NGS panel

CaseGenotypingMethod: CORD NGS panel - ABCA4, ADAM9, AIPL1, C8orf37, CFAP410 (C21orf2), CACNA1F, CACNA2D4, CDHR1, CEP78, CNGA3, CRX, DRAM2, GUCA1A, GUCY2D, UNC119, IFT81, KCNV2, PDE6C, PITPNM3, POC1B, PROM1, PRPH2, RAB28, RAX2, RIMS1, RPGR, RPGRIP1, SEMA4A, TTLL5.

Variant: c.37del (p.Leu13Ter) homozygous

ClinVar: N/A

CAID: CA2860243

gnomAD: The highest MAF in gnomAD v2.1.1 is 0.00003019 in European non-Finnish (no homozygotes in any population)

VariantEvidence: The variant would either result in nonsense-mediated mRNA decay, or retain few of the structural elements required for correct folding, causing degradation.

CaseAddInfo: Patient 3 is the affected sister of Patient 2. She is affected but has a milder phenotype. The father of these individual is unaffected and heterozygous for the variant. No details are provided about the mother.

Case#: MD-0448 proband, female, 18 years old (report), Spain.

CaseHPOs: HP:0007663, HP:0011003, HP:0000651, HP:0007641 (decreased visual acuity, high myopia, diplopia, dyschromatopsia)

CaseHPOsFreeText: Onset at 8 years. BCVA, 0.5 on the Snellen-equivalent decimal scale [Snellen equivalent, 20/40]). Rapid deterioration of vision. BCVA progressed to 0.3 (Snellen equivalent, 20/65) at age 9 years and to 0.2 (Snellen equivalent, 20/100) at 12 years but stable since then. Fundus exam showed a tigroid fundus, bull’s eye maculopathy, thin vessels, peripapillary atrophy, and optic pallor. Peripheral retina appeared normal. Photopic responses were undetectable by ERG, and scotopic responses were residual. Visual-evoked potential recorded pathologic responses, including low amplitude and enlarged latency (implicit time).

CasePreviousTesting: Screened for variants in the ABCA4 gene by ABCA4 genotyping microarray.

CaseMethod1: WES

GenotypingMethod: WES found no pathogenic variants in the genes known to be associated with the arCRD phenotype (ABCA4, ADAM9, C8orf37, CERKL, EYS, RPGRIP1, and TULP1), and no other plausible genetic variant.

Variant: c.651T>G (p.Cys217Trp), homozygous (NM_001017979.3(RAB28):c.574-1238T>G)

ClinVar: 225879

gnomAD: The highest population minor allele frequency in gnomAD is 0.00002904 in the Latino/Admixed American population; no homozygotes in any population.

VariantEvidence: Present only in isoform 2.

CaseAddInfo: The parents and unaffected sibling are all heterozygous for the variant.

CA2860239Allele Registry