Usher syndrome in the United Arab Emirates.

PURPOSE: Usher syndrome, a common form of syndromic inherited retinal dystrophy in the Arabian Gulf, has not been molecularly defined in the United Arab Emirates. The current study addresses this gap in knowledge. METHODS: A retrospective case series of Emirati patients referred to the Ocular Genetics Clinic of Cleveland Clinic Abu Dhabi who (1) were clinically diagnosed with Usher syndrome and underwent genetic testing (whole exome sequencing, 2019 to 2023, inclusive) and (2) were identified to have biallelic pathogenic variants in Usher syndrome genes during the same time period. RESULTS: Ten probands (thirteen patients) were identified-seven probands (nine patients) with clinically diagnosed Usher syndrome and three additional probands (four patients) with biallelic homozygous USH2A variants. Among the seven probands initially diagnosed with Usher syndrome, six had different homozygous variants (three in MYO7A, one in ADGRV1, and one in CLRN1), one had dual diagnoses rather than Usher syndrome (i.e. separate cause for retinal dystrophy and deafness), and one had no identifiable genetic cause. Regarding the three additional probands identified with homozygous USH2A variants, all three had retinitis pigmentosa only rather than Usher syndrome and all three had different variants. DISCUSSION: Clinically diagnosed Usher syndrome was genetically heterogenous without evidence for founder effect in this Emirati cohort. MYO7A was the most common associated gene. Dual diagnosis rather than single cause can mimic Usher syndrome. Homozygous USH2A variants were not identified as a cause for Usher syndrome in this cohort but were a recurrent cause for retinitis pigmentosa without hearing impairment and without founder effect.

Paradoxical keratitis and dermatitis following adalimumab treatment.

Anti-tumor necrosis factor (TNF) monoclonal antibodies are an important tool in the management of rheumatologic disease. However, paradoxical inflammation can be precipitated by their use. This case report describes the development of keratitis and dermatitis following adalimumab treatment for chronic recurrent multifocal osteomyelitis in a 6-year-old girl. The keratitis and dermatitis subsided once topical steroids were started and the adalimumab was held.

The genetic basis of clinically-suspected achromatopsia in the United Arab Emirates.

PURPOSE: Achromatopsia (ACHM) is a genetically heterogenous relatively stationary congenital autosomal recessive cone disorder characterized typically by photophobia, low vision, nystagmus, hyperopia, grossly normal retinal appearance, and absent photopic responses by full-field electroretinography. Incomplete forms occur as well. This study investigates the genetic basis of clinically-suspected ACHM in the United Arab Emirates. METHODS: Retrospective case series (January 2016-December 2023) of patients with (1) clinically-suspected ACHM and (2) mutations in ACHM-associated genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, AT6). RESULTS: Twenty-two clinically-suspected patients (19 probands) were identified. Biallelic disease genes and number of probands were CNGA3 (9), CNGB3 (6), PDE6C (1), GNAT2 (1), RGS9BP (1), and CNNM4 (1). Two probands had their diagnoses revised after genetic testing and phenotypic reassessment to RGS9BP-related bradyopsia and CNNM4-related Jalili syndrome. Three additional cases (making 22 total probands) were identified from ACHM gene mutation review - one each related to PDE6C, to AT6, and to CNGB3 in concert with CNGA3 (triallelic disease). All three presented with macular discoloration, an atypical finding for classic ACHM. CONCLUSION: CNGA3 was the single most frequent implicated gene. Bradyopsia and Jalili syndrome can resemble incomplete ACHM. Macular discoloration on presentation can occur in PDE6C-related disease, AT6-related disease, and triallelic CNGB3/CNGA3-related disease. The possibility for triallelic disease exists and requires genetic counseling beyond that of simple autosomal recessive inheritance.

Biallelic occult macular dystrophy.

PURPOSE: Occult macular dystrophy (OMD) is a cause of visual loss in young adults with a grossly normal fundus appearance. It is considered an autosomal dominant disorder, related to heterozygous pathogenic variants in the gene RP1L1. The purpose of this study is to report a biallelic form of the disease. RESULTS: A 29-year-old female had undergone neurological workup and ophthalmic examinations for transient visual loss in her left eye over the past two years but there was no definitive diagnosis. The best-corrected visual acuity was 20/30, 20/20. Indirect ophthalmoscopy with a 78D lens revealed subtle central retinal pigment epithelium mottling and optical coherence tomography confirmed subtle central thickening of the ellipsoid zone. Full-field electroretinography was normal, but pattern electroretinography showed decreased p50 responses. OMD was suspected. Retinal gene panel testing was significant only for a homozygous variant in RP1L1 (NM_178857.6: c.3571 G>T; p.Glu1191*). The parents and older brother were unavailable for segregation analysis. By history they did not have visual complaints other than a need for glasses. CONCLUSIONS: This report presents the clinical and genetic findings of a biallelic form of OMD associated with a novel pathogenic variant in RP1L1. It would be of interest to carefully assess macular function in heterozygotes with this variant.

A founder variant expands the phenotype of WNT7B-related PDAC syndrome.

Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia, and Cardiac defects (PDAC) syndrome is a genetically heterogeneous multiple congenital malformation syndrome. Although pathogenic variants in RARB and STRA6 are established causes of PDAC, many PDAC cases remain unsolved at the molecular level. Recently, we proposed biallelic WNT7B variants as a novel etiology based on several families with typical features of PDAC syndrome albeit with variable expressivity. Here, we report three patients from two families that share a novel founder variant in WNT7B (c.739C > T; Arg247Trp). The phenotypic expression of this variant ranges from typical PDAC features to isolated genitourinary anomalies. Similar to previously reported PDAC-associated WNT7B variants, this variant was found to significantly impair WNT7B signaling activity further corroborating its proposed pathogenicity. This report adds further evidence to WNT7B-related PDAC and expands its variable expressivity.

Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.

BACKGROUND: Long-read whole genome sequencing (lrWGS) has the potential to address the technical limitations of exome sequencing in ways not possible by short-read WGS. However, its utility in autosomal recessive Mendelian diseases is largely unknown. METHODS: In a cohort of 34 families in which the suspected autosomal recessive diseases remained undiagnosed by exome sequencing, lrWGS was performed on the Pacific Bioscience Sequel IIe platform. RESULTS: Likely causal variants were identified in 13 (38%) of the cohort. These include (1) a homozygous splicing SV in TYMS as a novel candidate gene for lethal neonatal lactic acidosis, (2) a homozygous non-coding SV that we propose impacts STK25 expression and causes a novel neurodevelopmental disorder, (3) a compound heterozygous SV in RP1L1 with complex inheritance pattern in a family with inherited retinal disease, (4) homozygous deep intronic variants in LEMD2 and SNAP91 as novel candidate genes for neurodevelopmental disorders in two families, and (5) a promoter SNV in SLC4A4 causing non-syndromic band keratopathy. Surprisingly, we also encountered causal variants that could have been identified by short-read exome sequencing in 7 families. The latter highlight scenarios that are especially challenging at the interpretation level. CONCLUSIONS: Our data highlight the continued need to address the interpretation challenges in parallel with efforts to improve the sequencing technology itself. We propose a path forward for the implementation of lrWGS sequencing in the setting of autosomal recessive diseases in a way that maximizes its utility.

Presumed uremic optic neuropathy in a patient with Senior-Loken syndrome.

A patient who had been diagnosed with infantile retinal dystrophy developed renal failure in his twenties, at which time the diagnosis was revised to Senior-Loken syndrome. He was poorly compliant. At 36 years old, he experienced a sudden drop in visual acuity in the setting of cramping and fatigue and was found to be in uremic crisis. Six months after the event and its treatment, his vision failed to improved. Optic nerve pallor was out of proportion to the retinal dystrophy, and the presumed reason for his new visual loss was uremic optic neuropathy. The patient's younger sister also had been diagnosed with infantile retinal dystrophy, and metabolic screening confirmed subclinical renal dysfunction that was to be carefully followed going forward. Infantile retinal dystrophy can be associated with later systemic disease. Early detection of such disease can potentially decrease morbidity. Patients with retinal dystrophy can develop new visual loss from causes other than the retinopathy itself.

Full-field electroretinography - when do we need it?

Multimodal imaging and genetic testing allow sophisticated assessment of suspected inherited retinal disease. Given the availability of such technology, some question whether the full-field electrogram (ffERG) is needed anymore. In fact, a ffERG remains essential for certain clinical scenarios. The goal of this case-based review is to provide a clear understanding of what clinical situations warrant a ffERG. All practicing ophthalmologists should be familiar with this information.

KCNV2-associated retinopathy: genotype-phenotype correlations - KCNV2 study group report 3.

BACKGROUND/AIMS: To investigate genotype-phenotype associations in patients with KCNV2 retinopathy. METHODS: Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants, electroretinography (ERG) and retinal imaging. Subjects were grouped according to the combination of KCNV2 variants-two loss-of-function (TLOF), two missense (TM) or one of each (MLOF)-and parameters were compared. RESULTS: Ninety-two patients were included. The mean age of onset (mean±SD) in TLOF (n=55), TM (n=23) and MLOF (n=14) groups was 3.51±0.58, 4.07±2.76 and 5.54±3.38 years, respectively. The mean LogMAR BCVA (±SD) at baseline in TLOF, TM and MLOF groups was 0.89±0.25, 0.67±0.38 and 0.81±0.35 for right, and 0.88±0.26, 0.69±0.33 and 0.78±0.33 for left eyes, respectively. The difference in BCVA between groups at baseline was significant in right (p=0.03) and left eyes (p=0.035). Mean outer nuclear layer thickness (±SD) at baseline in TLOF, MLOF and TM groups was 37.07±15.20 µm, 40.67±12.53 and 40.38±18.67, respectively, which was not significantly different (p=0.85). The mean ellipsoid zone width (EZW) loss (±SD) was 2051 µm (±1318) for patients in the TLOF, and 1314 µm (±965) for MLOF. Only one patient in the TM group had EZW loss at presentation. There was considerable overlap in ERG findings, although the largest DA 10 ERG b-waves were associated with TLOF and the smallest with TM variants. CONCLUSIONS: Patients with missense alterations had better BCVA and greater structural integrity. This is important for patient prognostication and counselling, as well as stratification for future gene therapy trials.

RPGRIP1-related retinal disease presenting as isolated cone dysfunction.

PURPOSE: Bialleic RPGRIP1 pathogenic variants are typically associated with severe Leber congenital amaurosis (non-recordable electroretinography [ERG]) and less commonly with cone-rod dystrophy. This report highlights isolated cone dysfunction as an alternative RPGRIP1-related presenting phenotype. METHODS: Retrospective case series. RESULTS: Four individuals (two sibships from two unrelated families) had low vision, nystagmus, photophobia, and a grossly normal retinal appearance since soon after birth. ERG confirmed non-recordable photopic function with normal scotopic function. Genetic testing revealed affected members from the two families to harbor two different homozygous RPGRIP1 variants (Family 1: c.3565C>T; p.Arg1189*; Family 2: c.2711_2741delinsATATTAG; p.Gly904_Lys914delinsAspIIeArg). Follow-up for Family 1 revealed deterioration of pan-retinal function (non-recordable ERGs by 11 and 7 years old) and thus a final diagnosis of cone-rod dystrophy. Follow-up for Family 2 showed stable retinal function (normal ERG scotopic tracings maintained at 12 and 21 years old) and thus a diagnosis of isolated cone dysfunction. CONCLUSIONS: Isolated cone dysfunction that progresses to pan-retinal dysfunction or remains relatively stationary is an alternative phenotype related to biallelic RPGRIP1 pathogenic variants.

LEPREL1 -RELATED GIANT RETINAL TEAR DETACHMENTS MIMIC THE PHENOTYPE OF OCULAR STICKLER SYNDROME.

PURPOSE: To describe the features of retinal detachments and high myopia in patients with novel pathogenic variants in LEPREL1 and report a possible association with nephropathy. METHODS: Retrospective study of 10 children with biallelic LEPREL1 pathogenic variants. Data included ophthalmic features, surgical interventions, and genetic and laboratory findings. RESULTS: 10 patients (8 females) from three families with homozygous (2) or compound heterozygous (1) variants in LEPREL1 were included. At presentation, mean age was 9.9 ± 2.6 years. Mean axial length was 28.9 ± 1.9 mm and mean refraction was -13.9 ± 2.8 diopters. Bilateral posterior subcapsular cataracts were present in eight patients (80%), with lens subluxation in five eyes of three patients (30%). Rhegmatogenous retinal detachments (RRD), associated with giant retinal tears (GRT), developed in seven eyes of five patients (50%) at a mean age of 14.14 ± 5.9 years. Six were successfully reattached with mean Snellen best-corrected visual acuity improving from 20/120 preoperatively to 20/60 at last follow-up. Urinalysis in nine patients revealed microhematuria and/or mild proteinuria in six patients (67%). CONCLUSION: LEPREL1 -related high myopia confers a high risk of early-onset GRT-related RRD. The ocular phenotype may be confused with that of ocular Stickler syndrome if genetic testing is not performed. Further investigations into a potential association with renal dysfunction are warranted.

The genomic landscape of rare disorders in the Middle East.

BACKGROUND: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans. METHODS: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant. RESULTS: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders. CONCLUSIONS: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.

Bi-allelic variants in WNT7B disrupt the development of multiple organs in humans.

BACKGROUND: Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects delineate the PDAC syndrome. We aim to identify the cause of PDAC syndrome in patients who do not carry pathogenic variants in RARB and STRA6, which have been previously associated with this disorder. METHODS: We sequenced the exome of patients with unexplained PDAC syndrome and performed functional validation of candidate variants. RESULTS: We identified bi-allelic variants in WNT7B in fetuses with PDAC syndrome from two unrelated families. In one family, the fetus was homozygous for the c.292C>T (p.(Arg98*)) variant whereas the fetuses from the other family were compound heterozygous for the variants c.225C>G (p.(Tyr75*)) and c.562G>A (p.(Gly188Ser)). Finally, a molecular autopsy by proxy in a consanguineous couple that lost two babies due to lung hypoplasia revealed that both parents carry the p.(Arg98*) variant. Using a WNT signalling canonical luciferase assay, we demonstrated that the identified variants are deleterious. In addition, we found that wnt7bb mutant zebrafish display a defect of the swimbladder, an air-filled organ that is a structural homolog of the mammalian lung, suggesting that the function of WNT7B has been conserved during evolution for the development of these structures. CONCLUSION: Our findings indicate that defective WNT7B function underlies a form of lung hypoplasia that is associated with the PDAC syndrome, and provide evidence for involvement of the WNT-ß-catenin pathway in human lung, tracheal, ocular, cardiac, and renal development.

PMEL is mutated in oculocutaneous albinism.

Oculocutaneous albinism (OCA) is a group of Mendelian disorders characterized by hypopigmentation of skin, hair and pigmented ocular structures. While much of the genetic heterogeneity of OCA has been resolved, many patients still lack a molecular diagnosis following exome sequencing. Here, we report a consanguineous family in which the index patient presented with OCA and Hirschsprung disease but tested negative for known genetic causes of OCA. Instead, he was found to have a homozygous presumptive loss of function variant in PMEL. PMEL encodes a scaffolding protein that is essential for the normal maturation of melanosomes and normal deposition of the melanin pigment therein. Numerous PMEL vertebrate ortholog mutants have been reported and all were characterized by conspicuous pigmentary abnormalities. We suggest that the patient we report is the first human equivalent of PMEL loss of function.

ADAMTS18-related anterior segment dysgenesis mistaken as Axenfeld-Rieger syndrome.

Axenfeld-Rieger spectrum is a range of anterior segment dysgenesis (ASD) phenotypes often related to heterozygous pathogenic variants in the ocular transcription factor genes FOXC1 or PITX2. Microcornea with myopic chorioretinal atrophy, a less common ASD, is distinct, recognizable, and secondary to biallelic pathogenic variants in the metalloproteinase gene ADAMTS18. This report describes the case of a boy with ADAMTS18-related ASD that was mistaken for Axenfeld-Rieger syndrome and highlights distinguishing features.

Congenital Cranial Dysinnervation Disorder Complicated by Ipsilateral Orbital Choriostoma.

A 20-year-old woman with right-sided congenital cranial dysinnervation disorder (exotropia, ophthalmoplegia, and ptosis) presented for strabismus surgery. Exploration of the right eye confirmed abnormal extraocular muscles. Lateral rectus recession with medial rectus plication and inferior oblique recession improved primary position ocular alignment. However, an unusual pattern of inferior chemosis developed postoperatively and persisted during the next month. Excision and histologic examination of this tissue revealed areas of lacrimal gland and cartilage with surrounding inflammation, suggestive of a disrupted orbital choriostoma. [J Pediatr Ophthalmol Strabismus. 2022;59(6):e66-e68.].

Anterior segment dysgenesis: Insights into the genetics and pathogenesis.

Childhood glaucoma is a treatable cause of blindness, provided it is recognized, diagnosed, and treated in time. WHO has estimated that it is responsible for Blind Years second only to cataracts. The fundamental pathophysiology of all childhood glaucoma is impaired outflow through the trabecular meshwork. Anterior segment Dysgeneses (ASD) are a group of non-acquired ocular anomalies associated with glaucoma, characterized by developmental abnormalities of the tissues of the anterior segment. The cause is multifactorial, and many genes are involved in the development of the anterior segment. Over the last decade, molecular and developmental genetic research has transformed our understanding of the molecular basis of ASD and the developmental mechanisms underlying these conditions. Identifying the genetic changes underlying ASD has gradually led to the recognition that some of these conditions may be parts of a disease spectrum. The characterization of genes responsible for glaucoma is the critical first step toward developing diagnostic and screening tests, which could identify individuals at risk for disease before irreversible optic nerve damage occurs. It is also crucial for genetic counseling and risk stratification of later pregnancies. It also aids pre-natal testing by various methods allowing for effective genetic counseling. This review will summarize the known genetic variants associated with phenotypes of ASD and the possible significance and utility of genetic testing in the clinic.