ABSTRACT Introduction Short stature, optic atrophy, and Pelger-Huët anomaly (SOPH) syndrome is a rare autosomal recessive condition associated with variants in the NBAS gene. First described in 2010, SOPH syndrome is a relatively newly recognized condition and our understanding of the range of its manifestations and the variable expressivity of its features continues to evolve. A total of 110 cases of SOPH syndrome have been published in the literature to date, 93 of which were published in two case series reporting on the Yakut population. Methods Case report and review of literature. Results We present a case of a 25-year-old female with a prior clinical diagnosis of cone-rod dystrophy, who was found to have incomplete SOPH syndrome associated with a paternally inherited splice site variant and a maternally inherited complete NBAS gene deletion. This is the first report of SOPH syndrome without Pelger-Huët anomaly. Discussion Our case expands the phenotypic and genetic spectrum of SOPH syndrome. Similarly to many other syndromic conditions, SOPH can display variable expressivity of disease features. Furthermore, our patient’s complete deletion of one copy of the NBAS gene provides a unique opportunity to investigate in isolation the effects of the NBAS splice site variant found on the other allele.

ABSTRACT Introduction Inherited retinal diseases (IRDs) are a leading cause of vision loss. Lack of awareness and reimbursement may prevent timely genetic testing, leading to delays in diagnosis, genetic counseling, and impeding life planning. We assessed healthcare costs and resource utilization (HCRU) relative to the timing of the genetic test. Methods Patients with a clinical IRD diagnosis who underwent a genetic test from 2017–June 2023 were identified from Optum’s de-identified Clinformatics® Data Mart Database. Early testing was a genetic test ≤12 months, and Delayed Testing >12 months, after the first (index) ocular/retinal disorder diagnosis. All-cause HCRU from index until first genetic test date was assessed. Results 310 patients were included; 52.6% in the Early Test (mean age 45 ± 21.9 years), 47.4% in the Delayed Test groups (54 ± 22.5 years). Median time from index to genetic test was 101 and 847 days, respectively, with corresponding mean all-cause healthcare costs of $9,073 (±$24,258) and $75,553 (±$128,716), and mean ocular/retinal disorder-related costs of $2,899 (±$6,383) and $10,946 (±$32,801). The mean cost of genetic testing was US$585/patient. Conclusions Patients undergoing delayed vs early genetic testing incurred substantially higher HCRU. The cost to payers of genetic testing was markedly lower than the costs incurred when testing was delayed.

ABSTRACT Purpose Birt–Hogg–Dubé (BHD) syndrome 1 is caused by pathogenic folliculin (FLCN) variants, resulting in classic hair follicle tumors, pulmonary cysts, pneumothorax, and renal cancer. FLCN is expressed in retinal tissues, and previous reports of BHD described flecked chorioretinopathy, choroidal melanoma, chorioretinal atrophy, and retinal pigment epithelium microdetachments. FLCN has been implicated in numerous cellular processes of metabolism, autophagy, differentiation, ciliary function, and cellular adhesion. Methods and Findings We performed a retrospective chart review of clinical information and imaging of patients with BHD from three centers and describe three patients who were found to have diffuse, abnormal, pinpoint foci observed across multiple retinal imaging modalities in both eyes (n = 6 eyes). These lesions were hypo- and hyperautofluorescent on fundus autofluorescence (FAF) and hypo- and hyperfluorescent on fluorescein angiography. Optical coherence tomography (OCT) revealed loss of inner retinal laminations, and numerous pinpoint hyperreflective lesions throughout the inner, middle, and outer retina which were seen in foveal, perifoveal, and peripheral retinal sections. Conclusions Mild retinal disorganization across multiple imaging modalities expands the ocular phenotype of BHD and likely arises from defects in cellular adhesion mediated by FLCN. Larger cohorts of patients with BHD may be necessary to establish these ocular imaging abnormalities as part of the BHD phenotypic spectrum.

ABSTRACT Background The 2p duplication syndrome is a rare clinically heterogeneous disorder that arises from non-recurrent chromosomal rearrangements involving ~6 Mb up to ~90 Mb. The patients are characterized by a wide range of symptoms, including developmental delay, intellectual disability, distinctive facial features, congenital heart defects, and various ophthalmic manifestations. Case presentation We report a male newborn with maternally inherited unbalanced translocations resulting in partial trisomy of chromosome 2p (33.9 Mb) - 46,XY,der(10)t(2;10)(p22.3;p1?5)dmat. Fluorescence in situ hybridization and chromosomal microarray analyses confirmed three copies of 2p25.3-p22.3 region, encompassing 51 known disease-causing genes. The patient presented with low birth weight, ventricular septal defect, camptodactyly of the 3rd digit of the left hand and mild early feeding problems. Ophthalmological assessment revealed macular and optic nerve hypoplasia. MRI demonstrated hypoplasia of the optic chiasm and optic nerves, and partial agenesis of falx cerebri. Conclusion We describe macular and optic nerve hypoplasia in a patient with a novel chromosomal rearrangement resulting in 2p partial trisomy and provide an overview of 17 previously reported cases presenting ocular abnormalities. A broad variability of ophthalmological phenotypes has been observed, further expanded by the current report.

ABSTRACT Purpose Two patients with a suspected inherited retinal dystrophy (IRD) were referred to a specialist ophthalmology clinic for genetic testing to determine the cause of their disease. Case Report A 50-year-old female patient (P1) presented with retinitis pigmentosa and poor vision since childhood. Molecular genetic testing in P1 revealed two novel pathogenic variants in PHYH (NM_006214.4): p.(Val93*) and p.(Asn71Ilefs*23). A 57-year-old male patient (P2) presented with pigmentary changes at the macula. Molecular genetic testing in P2 revealed two novel variants in PHYN: p.(Phe183Ser) and c.2461G>C (splice acceptor). Both patients were referred to the metabolic disease clinic and phytanic acid levels were found to be 256 µg/mL in P1 (normal is < 3 µg/mL) and 48.2 µmol/L in P2 (normal is < 2.2 µmol/L) confirming the diagnosis of Refsum disease. Both patients shared systemic features of the disease including bilaterally abnormal metatarsals and dry skin, while P1 also had characteristic anosmia, kidney disease, peripheral neuropathy and mild hearing impairment. Conclusion We document for the first time an association between macular dystrophy and Refsum disease. Early diagnosis is important so that diet can be modified to improve prognosis for the complications associated with Refsum disease, although improvements in vision, slowing the retinal degeneration and overcoming refractory miosis, are less achievable.

ABSTRACT Purpose To assess the detectability of the pathogenic RP1 Alu insertion using the PrismGuide™ inherited retinal dystrophy (IRD) panel, which targets 82 IRD genes, and whole-exome sequencing (WES). Methods A girl diagnosed with early-onset retinitis pigmentosa at age 7 underwent IRD panel testing and WES at age 15. Sequencing data from both platforms were evaluated using standard automated pipelines and manually reviewed with the Integrative Genomics Viewer (IGV). PCR and Sanger sequencing were performed for confirmation. Results Automated pipelines for both the IRD panel and WES failed to detect any reportable pathogenic variants. However, IGV review revealed a markedly reduced read coverage within exon 4 of RP1 in both datasets, suggesting the homozygous Alu insertion. PCR and Sanger sequencing confirmed the presence of the insertion. Thus, both short-read sequencing approaches failed to identify the variant. Conclusions Short-read sequencing technologies, including the IRD panel and WES, have limitations in detecting short interspersed nuclear elements such as the RP1 Alu insertion. This case emphasizes the importance of manual IGV review and the necessity of confirmatory Sanger sequencing when such structural variants are suspected despite negative automated analyses.

ABSTRACT Purpose Familial exudative vitreoretinopathy (FEVR) is a category of vitreoretinal diseases with a broad phenotypic spectrum ranging from subclinical peripheral vascular changes to total retinal detachments. We report the clinical and molecular genetic findings in a 43-year-old patient whose ocular findings were consistent with retinitis pigmentosa but genetic testing indicative of FEVR. Methods The patient underwent serial examinations over a 12-year period that included fluorescein angiography, electroretinophysiologic testing, and molecular genetic testing using a retinal dystrophy panel. Results Repeated examinations demonstrated retinal pigmentary changes, arteriolar narrowing, and waxy disc pallor consistent with retinitis pigmentosa. Fluorescein angiography demonstrated peripheral non-perfusion, staining, and window defects, while electroretinogram and electro-oculogram were within normal limits. Genetic testing identified a novel heterozygous likely pathogenic nonsense variant in TSPAN12 gene, c.315T > A, p. (Cys105*). Conclusions This report highlights a novel TPSAN12 pathogenic variant causing atypical FEVR which manifests with a retinitis pigmentosa phenotype.

ABSTRACT Background Among the genes implicated in inherited retinal degenerations (IRDs), disease-causing variants in IDH3A have recently been reported, although they remain exceedingly rare. In some cases, these variants are associated with macular pseudocoloboma. IDH3A encodes the alpha subunit of the mitochondrial NAD+-dependent isocitrate dehydrogenase 3 (IDH3) complex, a key enzyme in the tricarboxylic acid (TCA) cycle. Methods Ophthalmic examination and whole-exome sequencing. Results We report the case of a 2-month-old female infant presenting with bilateral macular pseudocoloboma. Clinical examination showed age-appropriate visual behavior. Fundoscopy revealed well-defined atrophic lesions in the macula, retinal pigment epithelium (RPE) changes and vascular narrowing in both eyes. Whole-exome sequencing revealed that the patient appears to be homozygous for the NM_005530.3(IDH3A):c.364G>A (p.Ala122Thr) variant. Conclusion To our knowledge, this is the youngest reported patient with IDH3A-associated retinal dystrophy presenting with macular pseudocoloboma and expands the phenotypic spectrum of this disease.

ABSTRACT Introduction Enhanced S-cone syndrome (ESCS) is usually from biallelic pathogenic variants in NR2E3 (nuclear receptor subfamily 2 group E member 3). A less common cause is biallelic pathogenic variants in NRL (neural retina leucine zipper). When recordable, the ESCS electroretinogram (ERG) is pathognomonic. The diagnostic ERG features of ESCS do not include an electronegative waveform. The purpose of this study is to characterize ESCS in the United Arab Emirates (UAE). Methods Retrospective case series of patients diagnosed with ESCS at the Ocular Genetics Clinic of Cleveland Clinic Abu Dhabi (2016–2023, inclusive) who underwent confirmatory genetic analysis (of NR2E3 and, if negative, of NRL) Results Ten children (6 families) were identified. One child was homozygous for NR2E3: c.932G>A; p.Arg311Gln. The other 9 children (5 families) were homozygous for NRL: c.339C>G; p.Try113*. Seven children (4 families) had electroretinograms (ERGs), all of which were consistent with ESCS. Six of these children had an electronegative waveform, and they were all homozygous for the specific NRL variant. The child who did not have an electronegative waveform was homozygous for the NR2E3 variant. A literature review for published recordable ERGs in ESCS revealed additional NRL-related cases with an electronegative waveform but no NR23-related cases with an electronegative waveform. Conclusions NRL-related ESCS, related to homozygosity for NRL: c.339C>G; p.Try113*, is recurrent in the UAE and likely represents founder effect. The associated ERG includes an electronegative waveform. This finding may be a way to clinically distinguish NRL-related ESCS from NR2E3-related ESCS.