Objective To observe and analyze the gene mutation and clinical phenotype of patients with cone and rod dystrophy (CORD). MethodsA pedigree investigarion. Two CORD pedigrees including 2 patients and 6 family members were enrolled in Ningxia Eye Hospital of People' Hospital of Ningxia Hui Automous Region for this study. The patients were from 2 unrelated families, all of whom were probands. Take medical history with best-corrected visual acuity (BCVA), color vision, slit lamp microscopy, indirect ophthalmoscopy, fundus color photography, optical coherence tomography (OCT), autofluorescence (AF), fluorescein fundus angiography (FFA), electroretinogram (ERG). The peripheral venous blood of patients and their parents was collected, whole genome DNA was extracted, Trio whole genome exome sequencing was performed, Sanger verification and pedigree co-segregation were performed for suspected pathogenic mutation sites. According to the law of inheritance, family history was analyzed to establish its genetic type. Mutational loci pathogenicity was analyzed according to the American College of Medical Genetics (ACMG) guidelines and 4 online tools. ResultsTwo CORD families showed autosomal recessive inheritance. The proband of pedigree 1 was female, 49 years old. Binocular vision loss with photophobia lasted for 9 years and night blindness for 4 years. The BCVA of right eye and left eye were 0.03 and 0.06, respectively. The results of ERG showed that the amplitudes of dark adaptation 0.01 b-wave and dark adaptation 3.0 a-wave and b-wave in both eyes were slightly decreased, and the amplitudes of light adaptation 3.0 a-wave and b-wave were severely decreased. The proband of pedigree 2 was male, 30 years old. Vision loss in both eyes for 4 years. Denying a history of night blindness. The BCVA of right eye and left eye were 0.3 and 0.2, respectively. The results of ERG showed that the amplitudes of dark adaptation 0.01 b-wave and dark adaptation 3.0 a-wave and b-wave in both eyes were slightly decreased, and the amplitudes of light adaptation 3.0 a-wave and b-wave were severely decreased. The color of optic disc in both eyes was light red, the macular area was atrophic, the foveal reflection disappeared, and the peripheral retina was punctate pigmentation. The main fundus changes in 2 patients were macular atrophy. The proband of pedigree 1 carried compound heterozygous variations c.439-2A>G (M1) and c.676delT (p.F226fs) (M2) on CDHR1 gene. Her father and mother carried M2 and M1 heterozygous mutations, respectively. The proband of pedigree 2 carried compound heterozygous variations c.2665dupC (p.L889fs) (M3) and c.878T>C (p.L293P) (M4) on C2orf71 gene. His father and mother carried M4 and M3 heterozygous mutations, respectively. According to ACMG guidelines and on line tools, 4 variations were considered as pathogenic level. ConclusionsM1 and M2 of CDHR1 gene and M3 and M4 of C2orf71 gene are new pathogenic mutations of CORD. All patients presented with the clinical phenotype of decreased visual acuity and macular atrophy.
ObjectiveTo observe and determine the gene mutation site and clinical phenotype of a NDP gene mutant family, and provide a basis for the prenatal diagnosis of offspring. MethodsA pedigree investigation study. Two patients and 6 family members of a third-generation Han family with NDP gene mutation who were admitted to the Maternal and Child Health Hospital of Gansu Province from July 2019 to December 2021 were included in the study. The patients and their parents underwent the examination of pupil light reflex, strip light imaging, visual acuity evaluation, fundus color photography, and wide-field fluorescein fundus angiography (FFA). Peripheral blood of all the subjects was collected, the pathogenic genes were screened by whole exome sequencing, and NDP genes were detected by amplification of multiple ligated probes. DNA prenatal diagnosis was performed by amniocentesis at 19th weeks of the mother's third gestation.ResultsProband (Ⅲ1), male, 4 years old, full term natural delivery. At about 40 days after birth, B-mode ultrasonography indicated total retinal detachment in both eyes. Normal hearing and intelligence. Fundus examination was not performed. First sibling of proband (Ⅲ2, big younger brother), ophthalmologic examination 30 days after birth, retinal detachment in both eyes. Proband's mother (Ⅱ2) had unvascularized peripheral temporal retina in both eyes. Wide-angle FFA examination showed no vascularization of the peripheral temporal retina in both eyes, and slight leakage of peripheral vascular fluorescein. The proband's second sibling (Ⅲ3, little younger brother) was screened for neonatal eye disease 1 day after birth. No abnormalities were observed outside both eyes. Cornea and lens transparent. No abnormalities were observed in the optic disc and macula in both eyes. No vascular curvature was observed in the peripheral retina. The results of gene detection showed that there was hemizygote deletion in exon 2 of NDP gene of the proband (Ⅲ1) and its big younger brother (Ⅲ2). His mother (Ⅱ2) had heterozygosity deletion in exon 2 of NDP gene. The phenotype and genetic test results of the proband's father (Ⅱ1), uncle (Ⅱ3), maternal grandfather (Ⅰ1) and maternal grandmother (Ⅰ2) were not abnormal. ConclusionsThe hemizygote deletion in exon 2 of NDP gene is a pathogenic variation in the native family. The clinical phenotypes of different genders are different. Prenatal diagnosis is an effective way to block hereditary diseases in families.
Choroideremia (CHM) is a rare inherited eye disease that leads to blindness. It is caused by pathogenic variants in the CHM gene and exhibits X-linked recessive inheritance. Affected males present with progressively worsening night blindness, visual field loss, and decreased central vision, which can cause blindness in middle age. Although female carriers typically exhibit mild symptoms, it is essential to understand their clinical features for early diagnosis of patients as well as genetic counseling of family members. Currently, the recognition and diagnosis rates of CHM among ophthalmologists in various regions and levels of hospitals in China still need to be improved. A standardized clinical pathway is needed to meet the diagnostic and treatment needs of patients. Led by the the Chinese Hereditary Ocular Disease Diagnosis and the Treatment Group and the Chinese Hereditary Ocular Disease Alliance, based on existing evidence both domestically and internationally, the Expert consensus on diagnosis and treatment of choroideremia (2024) has been compiled, systematically and comprehensively elaborating on the standardized clinical pathways for CHM. Interpreting the key points of this consensus will help highlight its core points and ideas, enhancing the standardization and effectiveness of the diagnosis and treatment of CHM by ophthalmologists from all levels of hospitals.
ObjectiveTo understand the significance of common gene variations in the diagnosis, treatment, and prognosis of papillary thyroid cancer (PTC). MethodThe literature relevant research on PTC gene variations both domestically and internationally was reviewed. ResultsThe most common genetic variations in the PTC in clinical studies included mutations or rearrangements in BRAF, TERT promoter, RAS, RET, and other genes, which had certain diagnostic value for PTC, but the drugs available for their treatment was relatively limited; Moreover, it had been found that multiple genes co-mutations were also common in the PTC, and the prognosis was often worse. ConclusionsBy sorting out the genetic variations in PTC, new ideas and methods are provided for the diagnosis, treatment, and prognosis of PTC. By detecting the types of genetic variations, the occurrence, development, and prognosis of PTC can be predicted, and personalized treatment plans can be developed for patients with PTC.
ObjectiveTo investigate and analyze the relationship between genotype and phenotype in patients with early-onset high myopia (eoHM) associated with hereditary eye diseases. MethodsA family-based study was conducted among 30 families diagnosed with eoHM at Department of Ophthalmology of People's Hospital of Ningxia Hui Autonomous Region from January 2022 to June 2023. Seven families (23.3%, 7/30), all probands, and their 14 parents were included. These seven families were unrelated. Detailed patient and family histories were collected. All participants underwent comprehensive ophthalmic examinations, including best-corrected visual acuity, color vision testing, fundus color photography, optical coherence tomography, fluorescein fundus angiography, and fundus autofluorescence imaging. Full-field electroretinography was performed in four cases. Peripheral venous blood samples were collected from patients and their parents for whole-genome DNA extraction and whole-exome sequencing. Potential pathogenic variants were identified, and their pathogenicity was analyzed and confirmed by Sanger sequencing. The pathogenicity of newly discovered gene variants was evaluated according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). Literature on previously reported eoHM associated with hereditary eye diseases was reviewed to analyze the relationship between variant genes and clinical phenotypes. ResultsAmong the seven families, three exhibited X-linked inheritance, two showed autosomal recessive inheritance, and two demonstrated autosomal dominant inheritance. All the patients were male. Among the seven patients, one case each was identified with congenital stationary night blindness (CSNB), Bornholm eye disease, X-linked retinitis pigmentosa (XL-RP), cone-rod dystrophy, Knobloch syndrome, familial exudative vitreoretinopathy (FEVR), and Stickler syndrome. Genetic testing revealed nine gene variants highly correlated with the observed phenotypes. The genetic testing results revealed that all patients were found to carry nine gene variants highly associated with the phenotype, including: a hemizygous missense variant NYX c.647A>T (p.N216I) (M1), an OPN1LW LIAVA haplotype variant (M2), a hemizygous frameshift variant RPGR c.3096_3097del (p.E1033RfsTer45) (M3), compound heterozygous variants TTLL5 c.1588_1589del (p.L531EfsTer24) and c.850G>C (p.D284H) (M4, M5), compound heterozygous variants COL18A1 c.2118dup (p.G707RfsTer23) and c.3523_3524del (p.L1175VfsTer72) (M6, M7), a heterozygous missense mutation FZD4 c.1499C>T (p.T500I) (M8), and a heterozygous frameshift variant COL11A2 c.966dup (p.T323HfsTer19) (M9). Among them, M2, M4, M5, M8 and M9 were newly discovered mutation sites, and M1, M3, M6 and M7 were known mutation sites. According to the classification standards and guidelines of genetic variation issued by ACMG, M2, M3, M4, M6, M7, and M9 were judged to be pathogenic variants, while M1, M5, and M8 were of unknown clinical significance. Through literature review, it was found that eoHM was more common among the clinical phenotypes of 4 types of hereditary retinal diseases, including CSNB, Stickler syndrome, FEVR and XL-RP. ConclusioneoHM is intricately associated with inherited eye diseases and may serve as the earliest indicator of such conditions.