OBJECTIVE: To explore the clinical characteristics and genetic basis of two Chinese pedigrees affected with Joubert syndrome. METHODS: Clinical data of the two pedigrees was collected. Genomic DNA was extracted from peripheral blood samples and subjected to high-throughput sequencing. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out for a high-risk fetus from pedigree 2. RESULTS: The proband of pedigree 1 was a fetus at 23⁺⁵ weeks gestation, for which both ultrasound and MRI showed "cerebellar vermis malformation" and "molar tooth sign". No apparent abnormality was noted in the fetus after elected abortion. The fetus was found to harbor c.812+3G>T and c.1828G>C compound heterozygous variants of the INPP5E gene, which have been associated with Joubert syndrome type 1. The proband from pedigree 2 had growth retardation, mental deficiency, peculiar facial features, low muscle tone and postaxial polydactyly of right foot. MRI also revealed "cerebellar dysplasia" and "molar tooth sign". The proband was found to harbor c.485C>G and c.1878+1G>A compound heterozygous variants of the ARMC9 gene, which have been associated with Joubert syndrome type 30. Prenatal diagnosis found that the fetus only carried the c.485C>G variant. A healthy infant was born, and no anomalies was found during the follow-up. CONCLUSION The compound heterozygous variants of the INPP5E and ARMC9 genes probably underlay the disease in the two pedigrees. Above finding has expanded the spectrum of pathogenic variants underlying Joubert syndrome and provided a basis for genetic counseling and prenatal diagnosis.
Female ; Humans ; Pregnancy ; Pedigree ; Cerebellum/abnormalities* ; Abnormalities, Multiple/diagnosis* ; Eye Abnormalities/diagnosis* ; Kidney Diseases, Cystic/diagnosis* ; Phosphoric Monoester Hydrolases/genetics* ; Retina/abnormalities* ; East Asian People ; Mutation

OBJECTIVE: To develop a few-shot learning (FSL) approach for classifying optical coherence tomography (OCT) images in patients with inherited retinal disorders (IRDs). METHODS: In this study, an FSL model based on a student-teacher learning framework was designed to classify images. 2,317 images from 189 participants were included. Of these, 1,126 images revealed IRDs, 533 were normal samples, and 658 were control samples. RESULTS: The FSL model achieved a total accuracy of 0.974-0.983, total sensitivity of 0.934-0.957, total specificity of 0.984-0.990, and total F1 score of 0.935-0.957, which were superior to the total accuracy of the baseline model of 0.943-0.954, total sensitivity of 0.866-0.886, total specificity of 0.962-0.971, and total F1 score of 0.859-0.885. The performance of most subclassifications also exhibited advantages. Moreover, the FSL model had a higher area under curves (AUC) of the receiver operating characteristic (ROC) curves in most subclassifications. CONCLUSION This study demonstrates the effective use of the FSL model for the classification of OCT images from patients with IRDs, normal, and control participants with a smaller volume of data. The general principle and similar network architectures can also be applied to other retinal diseases with a low prevalence.
Humans ; Tomography, Optical Coherence ; Deep Learning ; Retinal Diseases/diagnostic imaging* ; Retina/diagnostic imaging* ; ROC Curve

OBJECTIVES: To study the clinical and genetic features of Joubert syndrome (JS) in children. METHODS: A retrospective analysis was performed on the clinical data, genetic data, and follow-up data of 20 children who were diagnosed with JS in the Department of Children's Rehabilitation, the Third Affiliated Hospital of Zhengzhou University, from January 2017 to July 2022. RESULTS: Among the 20 children with JS, there were 11 boys and 9 girls. The common clinical manifestations were developmental delay (20 children, 100%), abnormal eye movement (19 children, 95%), and hypotonia (16 children, 80%), followed by abnormal respiratory rhythm in 5 children (25%) and unusual facies (including prominent forehead, low-set ears, and triangular mouth) in 3 children (15%), and no limb deformity was observed. All 20 children (100%) had the typical "molar tooth sign" and "midline cleft syndrome" on head images, and 6 children (30%) had abnormal eye examination results. Genetic testing was performed on 7 children and revealed 6 pathogenic genes, i.e., the CPLANE1, RPGRIP1L, MKS1, CC2D2A, CEP120, and AHI1 genes. CONCLUSIONS For children with developmental delay, especially those with abnormal eye movement and hypotonia, it is recommended to perform a head imaging examination to determine the presence or absence of "molar tooth sign" and "midline cleft syndrome", so as to screen for JS to avoid missed diagnosis and misdiagnosis. There are many pathogenic genes for JS, and whole-exome sequencing can assist in the diagnosis of JS.
Male ; Female ; Humans ; Child ; Cerebellum ; Abnormalities, Multiple/genetics* ; Kidney Diseases, Cystic/genetics* ; Eye Abnormalities/genetics* ; Retina ; Retrospective Studies ; Muscle Hypotonia/genetics*

OBJECTIVE: To analyze the phenotype and genetic variant of a fetus with dysplasia of cerebellar vermis. METHODS: Gestational status and family history of the gravida was taken in combination with the imaging results of the fetus. Following elected abortion, fetal tissue and peripheral blood samples of the couple were collected for the extraction of genome DNA. Whole exome sequencing was carried out to screen potential variant associated with the phenotype of the proband. Specific PCR primers were designed to verify the results by Sanger sequencing. RESULTS: Prenatal ultrasound revealed that the fetal vermis cerebellum was poorly developed, which was similar to the previous pregnancy. Whole exome sequencing revealed that the fetus has carried compound heterozygous variants of the CPLANE1 gene, namely c.7978C>T and c.7169delT, which were respectively inherited from the husband and wife. CONCLUSION The c.7978C>T and c.7169delT compound heterozygous variants of the CPLANE1 gene probably underlay the dysplasia of cerebellar vermis in the fetus, which has provided a basis for genetic counseling and prenatal diagnosis.
Abnormalities, Multiple/genetics* ; Cerebellum/diagnostic imaging* ; Eye Abnormalities/genetics* ; Female ; Fetus ; Humans ; Kidney Diseases, Cystic ; Mutation ; Phenotype ; Pregnancy ; Retina/abnormalities*

OBJECTIVE: To explore the pathogenesis of two siblings (including a fetus) from a pedigree affected with Joubert syndrome. METHODS: Peripheral blood samples of the proband and his parents as well as amniotic fluid and abortion tissues of the fetus were collected. Part of the samples were used for the extraction of DNA, and whole exome sequencing (WES) was carried out to screen potential variants in the proband and his parents. Suspected variants were subjected to bioinformatics analysis with consideration of the clinical phenotype, and were verified by Sanger sequencing of the proband, fetus and their parents.The remainders were used for the extraction of RNA, and the mechanism of splicing variant was validated by reverse transcription-PCR (RT-PCR). RESULTS: WES showed that both patients have carried c.175C>T (p.R59X) and c.553+1G>A compound heterozygous variants of the TMEM237 gene. Among these, c.175C>T was a nonsense mutation inherited from the asymptomatic mother, while c.553+1G>A was an alternative splicing mutation inherited from the asymptomatic father. RT-PCR showed that this variant has resulted in aberrant splicing by exon skipping. CONCLUSION The compound heterozygous variants of the TMEM237 gene probably underlay the etiology of Joubert syndrome in this pedigree. Above finding has enriched the phenotype and variant spectrum of the TMEM237 gene, and facilitated genetic counseling and prenatal diagnosis for the family.
Abnormalities, Multiple/genetics* ; Cerebellum/abnormalities* ; Eye Abnormalities ; Female ; Genotype ; Humans ; Kidney Diseases, Cystic ; Mutation ; Pedigree ; Phenotype ; Pregnancy ; Retina/abnormalities*

OBJECTIVE: To identify pathogenic variants in two families with patients suspected for Joubert syndrome(UBST) by cerebellar vermis hypoplasia. METHODS: Clinical data and peripheral venous blood and skin tissue samples were collected for the extraction of genomic DNA. Potential variants were screened by using targeted capture and next generation sequencing. Suspected variants were validated by PCR and Sanger sequencing. The frequency of the variants in the population was calculated. Pathogenicity of the variants was predicted by following the guidelines of the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was provided to these families upon subsequent pregnancy. RESULTS: The proband of family 1 was found to harbor homozygous c.2072delT (p.F691S*fs19) frameshift variant of the AHI1 gene, which may cause premature termination of translation of the Abelson helper integration site 1 after the 691st amino acid. The proband of family 2 was found to harbor compound heterozygous variants of the CPLANE1 gene, namely c.7243dupA (p.T2415Nfs*7) and c.8001delG (p.K2667Nfs*31), which can respectively lead to premature termination of translation of ciliogenesis and planar polarity effector 1 after the 2145th and 2667th amino acids. All of the three variants were previously unreported, and were predicted to be pathogenic by bioinformatic analysis. CONCLUSION The AHI1 c.2072delT and CPLANE1 c.7243dupA and c.8001delG variants probably underlay JBTS3 in family 1 and JBTS17 in family 2, respectively. Based on above results, prenatal diagnosis may be offered to the affected families upon their subsequent pregnancies.
Abnormalities, Multiple ; diagnosis ; genetics ; Adaptor Proteins, Vesicular Transport ; genetics ; Cerebellum ; abnormalities ; Eye Abnormalities ; diagnosis ; genetics ; Female ; Genetic Testing ; Genetic Variation ; Humans ; Kidney Diseases, Cystic ; diagnosis ; genetics ; Membrane Proteins ; genetics ; Mutation ; Pregnancy ; Prenatal Diagnosis ; Retina ; abnormalities

OBJECTIVE: To explore the pathogenesis of two fetuses from one family affected with Joubert syndrome (JS). METHODS: Whole exome sequencing was employed to screen potential mutations in both fetuses. Suspected mutations were verified by Sanger sequencing. Impact of intronic mutations on DNA transcription was validated by cDNA analysis. RESULTS: Two novel TCTN1 mutations, c.342-8A>G and c.1494+1G>A, were identified in exons 2 and 12, respectively.cDNA analysis confirmed the pathogenic nature of both mutations with interference of normal splicing resulting in production of truncated proteins. CONCLUSION The genetic etiology of the family affected with JS has been identified.Above findings have enriched the mutation spectrum of TCTN1gene and facilitated understanding of the genotype-phenotype correlation of JS.
Abnormalities, Multiple ; diagnosis ; genetics ; Cerebellum ; abnormalities ; Eye Abnormalities ; diagnosis ; genetics ; Humans ; Kidney Diseases, Cystic ; diagnosis ; genetics ; Membrane Proteins ; genetics ; Mutation ; Pedigree ; Retina ; abnormalities ; Whole Exome Sequencing

PURPOSE: We report a case of fundus albipunctatus discovered in a young patient. CASE SUMMARY: A 7.6-year-old female showed numerous small whitish-yellow flecks in the perimacular area and retinal periphery. Dark adapted 0.01 electroretinography (ERG) and dark adapted 3.0 ERG were profoundly reduced. At 26 months after the first visit, the best-corrected visual acuities were 1.0 right eye and 0.9 left eye. There were no pigmented lesions, atrophic lesions, or vascular abnormalities in the retina. Humphrey and Goldmann visual field tests were performed, but neither of the tests revealed any scotomas or other visual field defect. The number and size of characteristic numerous small whitish-yellow retinal flecks seemed almost unchanged. In spectral domain-optical coherence tomography (SD-OCT), the subretinal hyper-reflective lesions spanned the retinal pigment epithelium and the external limiting membrane. ERG showed improved dark adapted responses (dark adapted 0.01 ERG and dark adapted 3.0 ERG) after prolonged dark adaptation (2.5 hours). No family member showed any abnormal findings. CONCLUSIONS: Fundus albipunctatus is a rare disease in Koreans. We report a case diagnosed using fundus photography, SD-OCT, visual field tests, and ERG after prolonged dark adaptation (2.5 hours).
Child ; Dark Adaptation ; Electroretinography ; Female ; Humans ; Membranes ; Photography ; Rare Diseases ; Retina ; Retinal Pigment Epithelium ; Retinaldehyde ; Scotoma ; Tomography, Optical Coherence ; Visual Acuity ; Visual Field Tests ; Visual Fields

PURPOSE: To report a case of orbital apex syndrome (OAS) combined with central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) following blunt trauma. CASE SUMMARY: A 4-year-old female visited the hospital following a traffic accident. She was admitted because of multiple fractures of the skull and pneumocephalus. On day 5, she was referred to us with decreased visual acuity in her right eye. Her initial visual acuity was hand motions in the right eye and 0.8 in the left eye. The right eye showed a dilated pupil, ptosis, and total ophthalmoplegia, and the left eye showed limited abduction. A fundus examination revealed multiple retinal hemorrhages, tortuous veins, and an edematous white retina with a cherry-red spot in the right eye. Brain magnetic resonance imaging revealed an entrapped right optic nerve because of bony fragments in the orbital apex. The patient was diagnosed with OAS accompanied by CRAO and CRVO in the right eye, and with traumatic abducens nerve palsy in the left eye. After 6 months, the visual acuity was hand motions, and the fundus examination showed absorbed retinal hemorrhages, pale discs, and general retinal thinning of the right eye. Ptosis of the right eye and extraocular muscle movement of both eyes were improved. CONCLUSIONS: Combined CRAO and CRVO following trauma is very rare and is even more rarely associated with OAS. It is important for clinicians to be aware of the potential for central retinal vessel occlusions and OAS in cases of blunt ocular trauma.
Abducens Nerve Diseases ; Accidents, Traffic ; Brain ; Child, Preschool ; Female ; Fractures, Multiple ; Hand ; Humans ; Magnetic Resonance Imaging ; Ophthalmoplegia ; Optic Nerve ; Orbit ; Pneumocephalus ; Pupil ; Retina ; Retinal Artery Occlusion ; Retinal Artery ; Retinal Hemorrhage ; Retinal Vein ; Retinal Vessels ; Retinaldehyde ; Skull ; Veins ; Visual Acuity

Hydroxychloroquine (HCQ) has been used widely for the treatment of several rheumatologic and dermatologic conditions, including systemic lupus erythematosus and rheumatoid arthritis. Its toxic effects on the retina, HCQ retinopathy, is not uncommon among long-term users, and produces characteristic irreversible and progressive outer retinal damage. Recent studies of Asian populations showed different patterns of retinopathy according to ethnicity; for example, a pericentral pattern is more common in Asian populations, whereas the parafoveal type is more prevalent in Caucasian patients. The pericentral pattern, which is common in Asian patients, is likely to lead to a late diagnosis with conventional imaging modalities, thereby necessitating increased attention to the screening of Asian patients. The most recent American Academy of Ophthalmology guidelines suggest optical coherence tomography and a visual field examination as the primary screening tests, and multifocal electroretinogram and fundus autofluorescence as other recommended objective screening tests. The optimal timing and frequency of annual screening depend on the systemic and ocular risk factors. Annual screening should begin from 5 years of drug use in cases without any known risk factors, but patients with major risk factors require earlier regular screening. After a diagnosis of HCQ retinopathy, a decision regarding whether to stop the drug should be made in consultation with the prescribing physician, and the progression of retinopathy should be monitored carefully because the retinopathy can progress even after drug cessation.
Arthritis, Rheumatoid ; Asian Continental Ancestry Group ; Delayed Diagnosis ; Diagnosis ; Humans ; Hydroxychloroquine* ; Lupus Erythematosus, Systemic ; Mass Screening ; Ophthalmology ; Retina ; Retinal Diseases ; Retinaldehyde ; Risk Factors ; Tomography, Optical Coherence ; Visual Fields