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.