Fig 2: Representative ophthalmological pictures of individuals carrying c.449T>C p.(Leu150Ser) in CEP78 (F1, III:2 and III:5). Clockwise from top left: (a) Composite fundus image of OD of male patient aged 53 (III:2). Severe reduction in vascular caliber, small white dots from the macula up to the midperiphery, relatively better preservation of fovea as well as peripheral retina, and spicular intraretinal pigmentation in nasal midperiphery. (b) Composite fundus picture of OS of female patient aged 47 (III:5). Virtually normal fundus except for mild reduction in vascular caliber. Abnormality of superonasal vessels to optic disc is composite artifact. (c) Blue light autofluorescence image of OS of III:5. Diffuse, mottled hyperautofluorescence is more pronounced in circle around central macula. (d) SD‐OCT of central macula of OS of III:5. Thinning of foveal area with considerable loss of definition of outer retinal layers (RPE and PRs). (e) SD‐OCT of central macula of OD of III:2. Thinning of outer retinal layers representing RPE and PRs, which are relatively better preserved in foveal area. Other retinal layers seem rather disorganized in the temporal macula. OD, oculus dexter (right eye); OS, oculus sinister (left eye); SD‐OCT, spectral‐domain optical coherence tomography; PR, photoreceptor; RPE, retinal pigment epithelium

Fig 3: (a) Structural modeling of the p.(Leu150Ser) CEP78 missense variant. Residues 106‐184 of the model of CEP78 N‐terminal domain (V42‐K198) based on an RNAse inhibitor structure were used as a template. In this model, Leu150 (L150, green) is surrounded by six other leucine residues (indicated with arrows). (b) Immunoblotting of endogenous CEP78 in primary fibroblasts. Since the p.(Leu150Ser) change is predicted to affect protein stability, protein levels of CEP78 were evaluated in available primary fibroblasts of F1 (II:2, II:8 and III:5) and F3 (II:1). Undetectable protein or strongly reduced CEP78 levels has been detected in the homozygous/compound heterozygous and heterozygous individuals, respectively. (c) Relative amounts of CEP78 were calculated on three independent western blots. Compared to controls, the amount of CEP78 is reduced in heterozygous carriers (p = .0075) and nearly undetectable in homozygous/compound heterozygous patients (p = .0048). M, mutation (in black: c.1462‐1G>T; in red: c.449T>C); +, wild type

Fig 4: Pedigrees segregating the CEP78 and SPAG17 variants, and haplotype reconstruction for the c.449T>C/p.(Leu150Ser) variant in CEP78. (a) F3, II:1 and II:2 are compound heterozygous for c.[449T>C]; [1462‐1G>T] p.[Leu150Ser];[?]. In F1, two variants p.(Pro1376LeufsTer8) and p.(Ala316Ser) were identified in SPAG17, occurring however in cis. (b) Haplotype reconstruction highlighted p.(Leu150Ser) in CEP78 as a founder allele. Complete haplotype is available in Table S10. M, mutant allele; +, wild‐type allele