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BACKGROUND/AAIMS: Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F, NYX and TRPM1. High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression. METHODS: This multicentre, retrospective study explored CSNB caused by variants in CACNA1F, NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated. RESULTS: 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F, NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F, NYX and TRPM1, respectively. CONCLUSIONS: Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia.
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In this report, we present a case of unilateral melanoma-associated retinopathy in a 72-year-old woman. The patient's main symptoms were decreased vision and positive dysphotopsia. Unilateral electronegative electroretinogram (ERG) was suggestive for melanoma retinopathy. PET-CT discovered metastatic disease, 3 years after the initial melanoma. A prompt treatment with corticosteroids was started, followed by immunotherapy. The central and peripheral vision of the patient improved, and the ERG showed normalization of the responses. This case highlights the importance of early recognition and individualized treatment strategies for melanoma-associated retinopathy.
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Objective: To describe a cohort of paediatric patients who underwent unilateral or bilateral lens extractions at Ghent University hospital using the Dutch Ophthalmic Research Center (D.O.R.C.) ultra-short 27G vitrectomy system. Methods: Retrospective analysis of the medical and surgical records of all children that underwent lens extraction between September 2016 and September 2020 using the D.O.R.C. ultra-short 27G vitrectomy system. Results: Seventy-two eyes of 52 patients were included. The most important aetiologies in this study were of secondary (25.5%), developmental (13.7%), or genetic (13.7%) nature. No definitive cause could be established in more than a quarter of cases (27.5%) despite extensive work-up, them being deemed idiopathic. The remainder of cases (19.6%) was not assigned a final aetiologic designation at the time of the study due to contradicting or missing diagnostic data. This study could not identify any cataract cases related to infection or trauma. Surgical complications rate was 61.1% of which posterior capsule opacification was the most frequent with a rate of 25%. A significant short-term postoperative best-corrected visual acuity gain (≤ -0.2 LogMAR) was observed in 60.5% of eyes for which usable acuity data were available (n = 38). Conclusion: Many different instruments and techniques have been described and used in the context of paediatric lens extractions, each with its advantages and disadvantages. This study illustrates that an ultra-short 27G vitrectomy system can be used to perform paediatric lens extractions with good surgical outcomes. Further studies and comparative trials are needed to ascertain this further.
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Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS, OMIM 615722) is a rare autosomal dominant disorder characterized by intellectual disability, optic atrophy, cortical visual impairment, mild facial dysmorphism, hypotonia, hearing problems, attention deficit and a thin corpus callosum. The gene underlying this disorder is NR2F1 located on chromosome 5q15 which encodes for a nuclear receptor protein. Mutations and deletions have been identified in patients. Here we report on a brother and a sister carrying a pathogenic nonsense NR2F1 variant. The patients have a mild phenotype showing optic atrophy, mild intellectual disability, dysmorphic features and thin corpus callosum. This correlates with previously described milder phenotypes in patients with mutations in this domain. The variant was not identified in the parental genome indicating most likely a gonadal mosaicism. Gonadal mosaicism has not yet been reported in Bosch-Boonstra-Schaaf Optic Atrophy Syndrome.
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Discapacidad Intelectual , Atrofias Ópticas Hereditarias , Atrofia Óptica , Masculino , Humanos , Hermanos , Discapacidad Intelectual/genética , Mosaicismo , Atrofias Ópticas Hereditarias/genética , Atrofia Óptica/genéticaRESUMEN
North Carolina macular dystrophy (NCMD) is a rare autosomal-dominant disease affecting macular development. The disease is caused by non-coding single-nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1. To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 promoters and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays. Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two NCMD-associated non-coding SNVs that we identified herein. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, suggesting that this region is a PRDM13 enhancer. Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis. Overall, this study provides insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.
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Distrofias Hereditarias de la Córnea , Tomografía de Coherencia Óptica , Adulto , Animales , Humanos , Linaje , Retina/metabolismo , Xenopus laevis/genéticaAsunto(s)
Ataxia Cerebelosa , Síndrome de Cogan , Miopía , Apraxias/congénito , Humanos , Mutación , Miopía/genética , LinajeRESUMEN
We investigated a possible association between the acute onset of esotropia and tablet or smartphone use in children. We characterized the clinical aspects of esotropia associated with tablet or smartphone use. The medical records of 10 children aged between 5 and 15 years old with presumably tablet or smartphone associated esotropia were reviewed regarding orthoptic examination and cycloplegic refraction. Legal guardians of the children were asked to fill in a questionnaire regarding tablet and smartphone use of their child. This questionnaire was also conducted in a control group of age-matched children. The results of this questionnaire were compared to search for possible determinants of tablet or smartphone associated esotropia. All 10 patients presented with a comitant esotropia ranging from 8 to 45 prism diopters with no significant difference between near and far. The mean age of onset was 9.8 years. Cycloplegic refraction showed a mild hyperopia in eight patients, a mild myopia in one patient and emmetropia in the other patient. All patients had near full refractive correction at the onset of esotropia. Diplopia was reduced after visual hygiene recommendations, however in six patients, strabismus surgery was needed. The working distance was significantly shorter in the 10 cases compared to the controls. In children with acute acquired esotropia, we found a statistically significant association with a smaller working distance during tablet or smartphone use compared to age-matched controls. We hypothesize that intensive near viewing can be a precipitating factor in this type of esotropia.
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Esotropía , Enfermedad Aguda , Adolescente , Niño , Preescolar , Esotropía/cirugía , Humanos , Midriáticos , Músculos Oculomotores/cirugía , Estudios Retrospectivos , Teléfono InteligenteRESUMEN
PURPOSE: To illustrate with multimodal imaging a case of HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) complicated by bilateral multifocal serous retinal detachments, subretinal exudation, and papilledema. METHODS: Case report. Fundus photography, spectral domain optical coherence tomography (SD-OCT), fluorescein angiography, and indocyanine green angiography were performed at presentation and the day after. We also present the SD-OCT follow-up at 8 days, 1 year, and 4 years. RESULTS: A 25-year-old 5-month-pregnant Guinean woman complained about decreased visual acuity in the right eye. Eye fundus and multimodal imaging were abnormal in both eyes. Spectral domain optical coherence tomography showed the presence of multifocal serous retinal detachments, subretinal deposits, and intraretinal cysts. Indocyanin green angiography revealed an irregular choroidal perfusion and localized choroidal ischemia. Spectral domain optical coherence tomography also provided assessment of retinal changes during the long-term follow-up, showing tissue damage in the outer retina. CONCLUSION: Serous retinal detachments during pregnancy can be the leading sign of HELLP syndrome-a potentially life-threatening condition. Spectral domain optical coherence tomography is a noninvasive and useful tool for its diagnosis and follow-up. ICG is important to confirm the choroidal ischemia and choroidal vascular abnormalities, underlying conditions leading to main sign of HELLP syndrome in the eye.
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Coriorretinopatía Serosa Central , Enfermedades de la Coroides , Síndrome HELLP , Desprendimiento de Retina , Enfermedades de la Retina , Coriorretinopatía Serosa Central/diagnóstico , Enfermedades de la Coroides/complicaciones , Enfermedades de la Coroides/diagnóstico por imagen , Femenino , Angiografía con Fluoresceína/métodos , Síndrome HELLP/diagnóstico , Humanos , Imagen Multimodal/métodos , Embarazo , Desprendimiento de Retina/diagnóstico por imagen , Desprendimiento de Retina/etiología , Enfermedades de la Retina/diagnóstico por imagen , Enfermedades de la Retina/etiología , Tomografía de Coherencia Óptica/métodosRESUMEN
Objective: Experimental evidence suggests that the clinical manifestations of Triple A syndrome result from oxidative stress. Several conditions caused by oxidative stress display retinal involvement. Our objective was to assess the retina and optic nerve involvement in children with Triple A syndrome. Methods: Eleven patients with genetically proven Triple A syndrome followed-up in our centre were approached for study participation. The main outcome was the measurement of the thicknesses of the different retinal layers by Optical Coherence Tomography (OCT). Results: 9 patients with triple A syndrome had OCT measurements. 7 patients were children and 2 were adults; 4 were females and 5 were males. The 7 paediatric patients had at least two OCT measured at a mean interval of 7.9 months after the first one. The average Retinal Nerve Fibre Layer thickness was 74 ± 10 µm in patients compared to the paediatric reference range of 100 ± 2 µm (p<0.05). Conclusions and Relevance: This is the first study to document retinal layer thicknesses in a series of patients with Triple A syndrome. Nearly all retinal thickness and peripapillary RNFL measurements were very significantly inferior to the reference range in Triple A patients, whatever their age. RNFL thinning was more marked at the temporal part of the optic nerve. OCT being non-invasive, it represents a promising tool to assess the severity of neurodegeneration in patients with Triple A syndrome.
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Insuficiencia Suprarrenal/complicaciones , Acalasia del Esófago/complicaciones , Enfermedades Neurodegenerativas/patología , Retina/patología , Tomografía de Coherencia Óptica/métodos , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Enfermedades Neurodegenerativas/etiología , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Traboulsi syndrome is a very rare, syndromic form of ectopia lentis that is potentially sight-threatening at a young age. It is characterized by typical facial, skeletal and ocular signs. MATERIALS AND METHODS: Two siblings, born to consanguineous parents, with a clinical phenotype consistent with Traboulsi syndrome, underwent extensive ophthalmic imaging and exome-based genetic testing. Both were treated with unilateral clear lens extraction via a limbal approach. RESULTS: Two siblings, one male and one female, presented with systemic and ocular features consistent with Traboulsi syndrome. Lens subluxation was present in all 4fouraffected eyes, and spontaneous subconjunctival bleb formation was detected in one eye. This eye also showed evidence of keratoconus-related corneal thinning. The clinical diagnosis of Traboulsi syndrome was confirmed molecularly. A homozygous, novel, pathogenic nonsense variant was identified in exon 25 of the ASPH gene: c.2181_2183dup, p.(Val727_Trp728insTer). Excellent visual outcomes following clear lens extraction and postoperative rigid gas-permeable contact lens fitting were obtained. CONCLUSIONS: We expanded the genetic spectrum of Traboulsi syndrome with a novel frameshift variant in the ASPH gene. We showed that lensectomy followed by gas-permeable contact lenses is an efficient therapeutic approach to treat lens subluxation in Traboulsi syndrome. However, lifelong follow-up is crucial to avoid (late) postoperative complications.
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Proteínas de Unión al Calcio/genética , Codón sin Sentido/genética , Anomalías Craneofaciales/genética , Desplazamiento del Cristalino/genética , Exones/genética , Iris/anomalías , Proteínas de la Membrana/genética , Oxigenasas de Función Mixta/genética , Proteínas Musculares/genética , Adolescente , Extracción de Catarata , Consanguinidad , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/fisiopatología , Anomalías Craneofaciales/cirugía , Desplazamiento del Cristalino/diagnóstico , Desplazamiento del Cristalino/fisiopatología , Desplazamiento del Cristalino/cirugía , Femenino , Humanos , Iris/fisiopatología , Iris/cirugía , Masculino , Hermanos , Microscopía con Lámpara de Hendidura , Agudeza Visual/fisiología , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: Heimler syndrome (OMIM number #234580 and #616617) is a rare condition comprising sensorineural hearing loss (SNHL), nail abnormalities and amelogenesis imperfecta. In addition, patients with this syndrome can have retinal dystrophies. Heimler syndrome is caused by bi-allelic pathogenic variants in the PEX1 or PEX6 gene. Only few patients with this syndrome have been reported. We hereby describe two siblings with genetically confirmed Heimler syndrome and provide imaging of the ocular phenotype. MATERIALS AND METHODS: The medical records of the siblings were reviewed retrospectively. RESULTS: Both brother and sister were diagnosed with SNHL and amelogenesis imperfecta of the permanent teeth; one of the affected siblings also had nail abnormalities. Both patients presented to the ophthalmology department with suboptimal visual acuity, fundus abnormalities and intraretinal cystoid spaces. Full-field electroretinogram revealed a cone-rod dysfunction. A genetic analysis revealed a homozygous likely pathogenic variant c.3077 T > C (p.Leu1026Pro) in the PEX1 gene in both siblings. The parents are heterozygous carriers of the variant. CONCLUSION: We recommend performing regular ophthalmic examination in patients with Heimler syndrome since the ophthalmic manifestations can manifest later in life. Our patients presented with cone-rod dystrophy and intraretinal cystoid spaces. Review of the literature shows that the ocular phenotype can be very variable in patients with Heimler syndrome.
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ATPasas Asociadas con Actividades Celulares Diversas/genética , Amelogénesis Imperfecta/genética , Distrofias de Conos y Bastones/genética , Pérdida Auditiva Sensorineural/genética , Edema Macular/genética , Proteínas de la Membrana/genética , Mutación , Uñas Malformadas/genética , Amelogénesis Imperfecta/diagnóstico por imagen , Amelogénesis Imperfecta/fisiopatología , Niño , Distrofias de Conos y Bastones/diagnóstico por imagen , Distrofias de Conos y Bastones/fisiopatología , Electrorretinografía , Femenino , Estudios de Seguimiento , Pérdida Auditiva Sensorineural/diagnóstico por imagen , Pérdida Auditiva Sensorineural/fisiopatología , Humanos , Edema Macular/diagnóstico por imagen , Edema Macular/fisiopatología , Masculino , Uñas Malformadas/diagnóstico por imagen , Uñas Malformadas/fisiopatología , Linaje , Retina/fisiopatología , Estudios Retrospectivos , Hermanos , Microscopía con Lámpara de Hendidura , Tomografía de Coherencia Óptica , Tonometría Ocular , Agudeza Visual/fisiologíaRESUMEN
PURPOSE: To investigate the natural history of RHO-associated retinitis pigmentosa (RP). METHODS: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP. RESULTS: Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field <20°) and blindness (central visual field <10°), respectively. For the best-corrected visual acuity (BCVA), the median age to reach mild impairment (20/67 ≤ BCVA < 20/40) was 72 years, whereas this could not be computed for lower acuities. Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005). The foveal thickness of the photoreceptor-retinal pigment epithelium (PR + RPE) complex correlated significantly with BCVA (Spearman's ρ = 0.733; P < 0.001). CONCLUSION: Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life. Significant differences in disease progression are present between generalized and sector RP phenotypes. Our findings suggest that the PR + RPE complex is a potential surrogate endpoint for the BCVA in future studies.
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Proteínas de Fase Aguda/genética , Predicción , Epitelio Pigmentado de la Retina/patología , Retinitis Pigmentosa/diagnóstico , Agudeza Visual , Campos Visuales/fisiología , Proteínas de Fase Aguda/metabolismo , Anciano , Electrorretinografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Retinitis Pigmentosa/sangre , Retinitis Pigmentosa/genética , Estudios Retrospectivos , Tomografía de Coherencia Óptica/métodosRESUMEN
Background: Knobloch syndrome (OMIM 267750) is a rare autosomal recessive disorder due to genetic defects in the COL18A1 gene. The triad of high myopia, occipital defect, vitreoretinal degeneration has been described as pathognomonic for this condition. Patients with Knobloch syndrome have also extraocular problems as brain and kidney malformations. High genetic and phenotypic variation has been reported in the affected patients.Materials and Methods: Here we provide detailed clinical description of 3 individuals with Knobloch syndrome. Ocular examination and fundus imaging have been performed. Detailed information about systemic conditions has been provided.Results: Mutations in COL18A1 were identified in all three patients. Patient 1 had congenital hip dislocation and patient 2 had renal atrophy, cardiac insufficiency and difficult skin healing.Conclusions: With this report we add to the clinical and genetic knowledge of this rare condition.
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Colágeno Tipo XVIII/genética , Encefalocele/patología , Mutación , Degeneración Retiniana/patología , Desprendimiento de Retina/congénito , Adolescente , Preescolar , Encefalocele/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Degeneración Retiniana/genética , Desprendimiento de Retina/genética , Desprendimiento de Retina/patologíaRESUMEN
Congenital microcoria (MCOR) is an eye anomaly characterized by a pupil with diameter below 2 mm, and is caused by underdevelopment or absence of the dilator muscle of the pupil. Two types have been described: a recessive, syndromic (Pierson syndrome OMIM 609049) and a dominant, isolated form (MCOR syndrome OMIM 156600). Fares-Taie and colleagues described inherited microdeletions in chromosome band 13q32.1 segregating with dominant microcoria in several families. The GPR180 gene is located within the smallest commonly deleted region and encodes a G protein-coupled receptor involved in smooth muscle cells growth. We here describe a patient with isolated, non-syndromic MCOR. The patient presented with a blue iris and small pupils, non-reactive to cycloplegic agents. Her mother had a milder ocular phenotype, namely a blue iris with hypoplastic crypts and mild myopia. We present a detailed clinical examination and follow up. DNA from the index patient was analyzed for the presence of chromosomal imbalances using molecular karyotyping. The genetic test revealed a small duplication of chromosome band 13q32.1. The duplication affected a 289 kb region, encompassing 11 genes including GPR180. Interestingly, the patient displays only MCOR in contrast to patients with the reciprocal deletion who present with MCOR and iridocorneal angle dysgenesis. This genetic anomaly was inherited from the mother who carries the duplication in mosaic form, which should be considered when offering genetic counselling. In summary, we describe the first 13q32.1 duplication encompassing GPR180 associated with MCOR.
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Duplicación Cromosómica , Cromosomas Humanos Par 13/genética , Trastornos de la Pupila/congénito , Receptores Acoplados a Proteínas G/genética , Adulto , Preescolar , Ojo/patología , Femenino , Humanos , Mosaicismo , Linaje , Trastornos de la Pupila/genética , Trastornos de la Pupila/patología , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
This study aimed to genetically and clinically characterize a unique cohort of 25 individuals from 21 unrelated families with autosomal recessive nanophthalmos (NNO) and posterior microphthalmia (MCOP) from different ethnicities. An ophthalmological assessment in all families was followed by targeted MFRP and PRSS56 testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct MFRP mutations were found in 10/21 families (47.6%), five of which are novel including a deletion spanning the 5' untranslated region and the first coding part of exon 1. Most cases harbored homozygous mutations (8/10), while a compound heterozygous and a monoallelic genotype were identified in the remaining ones (2/10). Six distinct PRSS56 mutations were found in 9/21 (42.9%) families, three of which are novel. Similarly, homozygous mutations were found in all but one, leaving 2/21 families (9.5%) without a molecular diagnosis. Clinically, all patients had reduced visual acuity, hyperopia, short axial length and crowded optic discs. Retinitis pigmentosa was observed in 5/10 (50%) of the MFRP group, papillomacular folds in 12/19 (63.2%) of MCOP and in 3/6 (50%) of NNO cases. A considerable phenotypic variability was observed, with no clear genotype-phenotype correlations. Overall, our study represents the largest NNO and MCOP cohort reported to date and provides a genetic diagnosis in 19/21 families (90.5%), including the first MFRP genomic rearrangement, offering opportunities for gene-based therapies in MFRP-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the MFRP and PRSS56 genes in MCOP and NNO.
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Alelos , Variaciones en el Número de Copia de ADN , Proteínas de la Membrana/genética , Microftalmía/genética , Mutación , Serina Proteasas/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Familia , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Secuenciación Completa del GenomaRESUMEN
Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.
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Alelos , Proteínas de Ciclo Celular/genética , Distrofias de Conos y Bastones/genética , Efecto Fundador , Pérdida Auditiva/genética , Infertilidad Masculina/genética , Mutación Missense , Adolescente , Proteínas de Ciclo Celular/química , Cilios/metabolismo , Cilios/ultraestructura , Distrofias de Conos y Bastones/diagnóstico , Análisis Mutacional de ADN , Femenino , Fibroblastos/metabolismo , Genotipo , Pérdida Auditiva/diagnóstico , Humanos , Infertilidad Masculina/diagnóstico , Masculino , Persona de Mediana Edad , Modelos Moleculares , Linaje , Fenotipo , Conformación Proteica , Relación Estructura-Actividad , Síndrome , Secuenciación del ExomaRESUMEN
Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.
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Canales de Calcio Tipo L/genética , Enfermedades Hereditarias del Ojo/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación , Miopía/genética , Ceguera Nocturna/genética , Análisis de Secuencia de ADN/métodos , Predisposición Genética a la Enfermedad , Hemicigoto , Humanos , Intrones , Masculino , Linaje , Empalme del ARN , Mutación SilenciosaRESUMEN
CONTEXT: The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, and an abnormal hypothalamus and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations have been reported to cause bilateral microphthalmia or anophthalmia without consistent associated features. Congenital hypopituitarism can be associated with various eye or craniofacial anomalies; however, the co-occurrence of congenital hypopituitarism, anophthalmia, cleft palate, and diabetes insipidus has been very rare. RESULTS: We report the case of a child with anophthalmia, congenital hypopituitarism, diabetes insipidus, and bilateral cleft lip and palate who had a homozygous frameshift truncating mutation c.266delC (p.Pro89Argfs*114) in exon 1 of the RAX gene. Rax knockout mice show loss of ventral forebrain structures, pituitary, and basosphenoid bone and palate and a misplaced anterior pituitary gland along the roof of the oral cavity. CONCLUSIONS: Our patient's phenotype was more severe than that reported in other patients. Although most of the previously reported patients with RAX mutations showed either a missense or some less severe mutation in at least one of their RAX alleles, our patient was homozygous for truncating mutations that would yield a severe, null protein phenotype. The severity of the genetic defect, the precise match between the knockout mouse and the patient's endocrine phenotypes, and the prominent roles of RAX in eye and pituitary development and diencephalic patterning suggest that the RAX null mutations could fully account for the observed phenotype.
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Anoftalmos/genética , Labio Leporino/genética , Fisura del Paladar/genética , Diabetes Insípida/genética , Proteínas del Ojo/genética , Proteínas de Homeodominio/genética , Hipopituitarismo/genética , Factores de Transcripción/genética , Animales , Anoftalmos/diagnóstico por imagen , Anoftalmos/patología , Fármacos Antidiuréticos/uso terapéutico , Labio Leporino/diagnóstico por imagen , Labio Leporino/patología , Fisura del Paladar/diagnóstico por imagen , Fisura del Paladar/patología , Desamino Arginina Vasopresina/uso terapéutico , Diabetes Insípida/diagnóstico por imagen , Diabetes Insípida/tratamiento farmacológico , Diabetes Insípida/patología , Mutación del Sistema de Lectura , Terapia de Reemplazo de Hormonas , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Hidrocortisona/uso terapéutico , Hipopituitarismo/diagnóstico por imagen , Hipopituitarismo/tratamiento farmacológico , Hipopituitarismo/patología , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Melatonina , Ratones Noqueados , Hipófisis/anomalías , Tiroxina/uso terapéuticoRESUMEN
PURPOSE: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. METHODS: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. RESULTS: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. CONCLUSION: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.
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Transportadoras de Casetes de Unión a ATP/genética , Genes Recesivos/genética , Oligonucleótidos Antisentido/genética , Distrofias Retinianas/genética , Adulto , Alelos , Estudios de Cohortes , Exones/genética , Femenino , Frecuencia de los Genes , Células HEK293 , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad , Mutación/genética , Oligonucleótidos Antisentido/farmacología , Linaje , Fenotipo , Distrofias Retinianas/patologíaRESUMEN
Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. Ten patients with Leber congenital amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. NCT03140969 ) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3 months. The visual acuity of one exceptional responder improved from light perception to 20/400.