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To reveal the clinical and genetic features of 54 Chinese pedigrees with syndromic or nonsyndromic retinal dystrophies related to CEP290 and to explore the genotype-phenotype correlation.Retrospective cohort study.Patients diagnosed with nonsyndromic inherited retinal dystrophy (IRD) or syndromic ciliopathy (SCP) were enrolled. We identified 61 patients from 54 families carrying biallelic pathogenic CEP290 variants using next-generation sequencing, Sanger sequencing, and co-segregation validation. Genotype-phenotype correlation was evaluated.This study included 37 IRD patients from 32 families and 24 patients with SCP from 22 pedigrees. Four retinal dystrophy phenotypes were confirmed: Leber congenital amaurosis (LCA, 46/61), early-onset severe retinal dystrophy (EOSRD, 4/61), retinitis pigmentosa (RP, 10/61), and cone-rod dystrophy (CORD, 1/61). The SCP phenotypes included Joubert syndrome (JS) (23/24) and Bardet-Biedl syndrome (BBS) (1/24). We detected 73 different CEP290 variants, of which 33 (45.2%) were not previously reported. Two novel copy number variations (CNVs) and one novel pathogenic synonymous change were identified. The most recurrent alterations in the IRD and SCP were p.Q123* (6/64, 9.4%) and p.I556Ffs*17 (10/44, 22.7%), respectively. IRD patients carried more stop-gain alleles (25/64, 39.1%), whereas SCP patients carried more frameshift alleles (23/44, 52.3%).LCA was the most common retinal dystrophy phenotype, and JS was the most prevalent syndrome in CEP290 patients; RP/CORD and BBS may be present in early adulthood. The hot spot variants and distribution of genotypes were distinct between IRD and SCP. Our study expands the CEP290 variant spectrum and enhances the current knowledge of CEP290 heterogeneity.

ARL2BP is a ciliary gene associated with multiple ciliopathy phenotypes. On comprehensive clinical examinations using molecular methods, we identified a Chinese patient from a consanguineous family carrying a novel homozygous variant c.22_23delAG (p.S8Lfs*10) in ARL2BP, presenting with retinitis pigmentosa (RP), situs inversus totalis, and oligozoospermia. Situs inversus and male infertility have never been reported in the same patient with ARL2BP variants; therefore, this a novel ARL2BP-associated phenotypic triad of RP, situs inversus, and male infertility. Moreover, this patient likely had olfactory dysfunction susceptibility and presented with anosmia. We found reduced patient-derived fibroblast proliferation and ciliary length. Our findings expand the genotypic spectrum and reveal abnormal cell proliferation and ciliogenesis in ARL2BP-associated patients.

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder, inherited by the defective SLC19A2 gene that encodes a high-affinity thiamine transporter (THTR-1). TRMA is characterized by the occurrence of classical triad manifestations including megaloblastic anemia, diabetes mellitus, and sensorineural deafness. In addition to the systemic manifestations, ophthalmic features can be present and include retinitis pigmentosa, optic atrophy, cone-rod dystrophy, maculopathy, and Leber congenital amaurosis. Here we report a 6-year-old boy presenting severe early-onset retinal dystrophy with the initial diagnosis of Leber congenital amaurosis, which followed for 12 years. Diabetes mellitus occurred 3 years after vision problem. Eosinophilic granuloma of the left scapula was confirmed at 13 years old. Whole-exome sequencing was performed to identify two novel compound heterozygous variants c.725dupC (p.Ala243Serfs*3) and c.121G>A (p.Gly41Ser) in SLC19A2 gene (NM_006996.3). Oral thiamine supplementation treatment was initiated at 13 years. This case demonstrates Leber congenital amaurosis can present as the first clinical feature before systemic manifestations. Phenotypic variety should be aware and multidisciplinary teamwork and regular follow-up are important for TRMA patient care.

Many transcription factors regulating the production, survival, and function of photoreceptor cells have been identified, but little is known about transcriptional co-regulators in retinal health and disease. Here, we show that BCL6 co-repressor (BCOR), a Polycomb repressive complex 1 factor mutated in various cancers, is involved in photoreceptor degenerative diseases. Using proteomics and transcription assays, we report that BCOR interacts with the transcription factors CRX and OTX2 and reduces their ability to activate the promoters of photoreceptor-specific genes. CUT&RUN sequencing further shows that BCOR shares genome-wide binding profiles with CRX/OTX2, consistent with a general co-repression activity. We also identify missense mutations in human BCOR in five families that have no evidence of cancer but present severe early-onset X-linked retinal degeneration. Last, we show that the human BCOR mutants cause degeneration when expressed in the mouse retina and have enhanced repressive activity on OTX2. These results uncover a role for BCOR in photoreceptors in both health and disease.

Many transcription factors regulating the production, survival, and function of photoreceptor cells have been identified, but little is known about transcriptional co-regulators in retinal health and disease. Here, we show that BCL6 co-repressor (BCOR), a Polycomb repressive complex 1 factor mutated in various cancers, is involved in photoreceptor degenerative diseases. Using proteomics and transcription assays, we report that BCOR interacts with the transcription factors CRX and OTX2 and reduces their ability to activate the promoters of photoreceptor-specific genes. CUTRUN sequencing further shows that BCOR shares genome-wide binding profiles with CRX/OTX2, consistent with a general co-repression activity. We also identify missense mutations in human

To elucidate the potential role of genetic polymorphisms of apolipoprotein E (APOE) in nonarteritic anterior ischemic optic neuropathy (NAION) and the association between APOE and NAION-induced ocular impairments.A total of 73 NAION patients and 73 sex- and age-matched healthy controls were recruited for the study. Genomic DNA was isolated from peripheral blood samples. The alleles and genotypes of APOE were explored. The interaction between APOE and medical comorbidities was assessed by the multifactor dimensionality reduction (MDR) method. Among 81 affected eyes of NAION patients, an additional association study of APOE isoforms with visual impairments was carried out.The allele and genotype frequencies for APOE showed significant differences when comparing NAION cases and controls. Multivariate analysis adjusted for age, sex, hypertension, dyslipidemia, diabetes mellitus, cardiovascular disease, and cerebrovascular disease revealed that the ε3/ε4 genotype (OR = 3.86, 95% CI = 1.13-13.25, p = 0.032) and ε4 allele (OR = 3.55, 95% CI = 1.05-11.99, p = 0.041) were strong independent risk factors for NAION. Compared to eyes with the ε3/ε3 + ε2/ε4 genotype, individuals with the ε4/ε4 + ε3/ε4 genotype had worse visual field defects (VFDs) and thinner macular ganglion cell complex (mGCC) thicknesses with larger focal loss of volume (FLV) and general loss of volume (GLV). Compared to ε4 noncarriers, ε4 carriers also tended to have more serious VFD and mGCC loss.APOE polymorphisms conferred a significant risk of NAION and were significantly related to ocular impairments caused by NAION.

The GUCY2D gene encodes the photoreceptor guanylate cyclase (GC-E) and different pathogenic variants can lead to Leber congenital amaurosis (LCA) or cone-rod dystrophy (CRD). In this study, we describe three unrelated families who carried different mutations at codon 838 of the GUCY2D gene, and presented different phenotypes of retinal degeneration. Family and personal histories were collected, and the patients underwent best corrected visual acuity (BCVA), fundus photography (FP), electroretinography (ERG), optical coherence tomography (OCT) and fundus autofluorescence (FAF). Venous blood was drawn from patients and family members, and genomic DNA was extracted. Next-generation sequencing of known ocular genes was applied to the proband to find pathogenic variants. Polymerase chain reaction (PCR) and Sanger sequencing were conducted for validation and segregation. Six patients from three unrelated families were enrolled. All the patients manifested decreased vision, photophobia and myopia from childhood. ERG recordings demonstrated a significant reduction in cone responses for all patients, while rod responses ranged widely from normal to moderately reduced. All patients were diagnosed with CRD, but the disease severity and progression rates in the three families were significantly different. Three pathogenic variants in the GUCY2D gene (c.2512 C > T (p.R838C), c.2512 C > A (p.R838S) and c.2513 G > A (p.R838H)) were identified. We presented the phenotypes of three Chinese adCRD families carrying different variants at codon 838 of the GUCY2D gene. The R838S variant is a novel genotype associated with GUCY2D-CRD. The R838H variant can cause severe retinal features. Our findings enhance the understanding of GUCY2D phenotypic diversity.

In the present work, a step die was made by P20 steel for squeeze casting magnesium alloy AZ91 with five different section thicknesses of 2, 4, 8, 12, and 20 mm under an applied pressure of 60MPa. ...

Lipid metabolic deficiencies are associated with many genetic disorders. Bietti crystalline dystrophy (BCD), a blindness-causing inherited disorder with changed lipid profiles, is more common in Chinese and Japanese than other populations. Our results reveal that mouse models lacking Cyp4v3 have less physiological and functional changes than those of BCD patients with this gene defect. After the administration of a high-fat diet (HFD), the occurrence of retinal lesions were both accelerated and aggregated in the Cyp4v3−/− mouse models, implying that changed lipid levels were not only associated factors but also risk factors to BCD patients. Facilitated by the results, we found that the reduced electroretinography waveforms and retinal thickness observed in the HFD-induced mouse models were effectively recovered after subretinal delivery of a human CYP4V2 gene carried by an adeno-associated virus vector, which demonstrates the potential curability of BCD by gene therapy.

Two types of Mg alloy AM60-based composites containing (1) only 7 vol.% Al2O3 Fibre and (2) both 7 vol.% Al2O3 Fibre + 3 vol.% Al2O3 nano-Particle, named 7FC and MHNC-7F3NP, respectively, as well a...

Usher syndrome 2A (USH2A) is one of the most common genes associated with Usher syndrome type II (USH2) and nonsyndromic autosomal recessive retinitis pigmentosa (arRP). Here, we describe the generation and characterization of two human induced pluripotent stem cell (hiPSC) lines from a RP patient with compound heterogeneous USH2A variants and a USH2 patient with homozygous USH2A variant. Blood samples were obtained and peripheral blood mononuclear cells (PBMCs) were reprogrammed using the non-integrative Sendai virus to generate the iPSC lines. The established hiPSC lines retained the disease-associated variants and showed normal karyotype, pluripotency and differentiation capacity.

North Carolina macular dystrophy (NCMD) is a rare autosomal dominant inherited disorder characterized by macular impairment with a variety of phenotypic manifestations. The aims of this study were to assess the clinical features of a Chinese family with NCMD and to identify the underlying genetic cause of the disease. Three patients from a Chinese family were included in this study. Detailed ophthalmological examinations were performed, including best corrected visual acuity (BCVA), slit lamp, dilated indirect ophthalmoscopy, fundus photography, optical coherence tomography (OCT), fundus autofluorescence, full-field electroretinography (ERG), and electrooculography (EOG). Genomic DNA was extracted from peripheral blood samples. Whole-genome sequencing and long-read genome sequencing were applied to detect the pathogenic variants. Sanger sequencing was performed to confirm the breakpoints. All three patients had macular involvement ranging from patchy yellowish-white lesions to big-area thinning, which are typical for NCMD. The BCVA ranged from 20/50 to 20/20. OCT revealed varying degrees of macular structure disorganization. The ERG responses were normal, and the Arden ration of the EOG was reduced. A novel 134.6 kb (g.99932464-100067110dup) tandem duplication on chromosome 6 (NC_000006.11) encompassing the entire CCNC and PRDM13 genes and a DNase 1 hypersensitivity site in the MCDR1 locus was identified. A novel large tandem duplication in MCDR1 locus was confirmed in a Chinese family with NCMD with a variety of macular phenotypes.

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessively inherited progressive retinal disease. Here, we describe the generation and characterization of a human induced pluripotent stem cell (hiPSC) line of BCD patient with CYP4V2 mutations. The reprogramming of this iPSC line was performed from skin fibroblast by using the Sendai-virus based approach. The established hiPSC line retained the disease-associated mutations and showed normal karyotype, pluripotency and differentiation capacity.

Zn-6 wt% Al hypereutectic alloy was melt in a mild steel crucible under a purge gas of nitrogen, and solidified with five different cooling rates of 0.04, 0.10, 0.22, 0.40, 10.00 °C/s. The influence of cooling rates on the solidification process of the alloy was investigated via thermal analyses based on temperature measurements recorded on cooling curves. The corresponding first and second derivatives of the cooling curves were derived to reveal the details of phase changes and the development sequences of microstructure features occurring during solidification. The microstructure analyses by scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) indicate that four different phases, the primary γ-ZnAl phase, the eutectic β-Zn phase, and the eutectoid α-Al and eutectoid β-Zn phases decomposed from the eutectic γ-ZnAl phase appear in all the samples solidified under the difference cooling rates. But, the quantitative analyses reveal that the decomposition rates of the primary γ-ZnAl and the average diameter of the eutectoid phases are reduced with increasing the cooling rates. The highest cooling rate of 10.00 °C/s suppresses the growth of the eutectoid phases and led to the formation of the nano-sized eutectoid α-Al and eutectoid β-Zn phases, and consequently refined the microstructure significantly.

TheFamily and personal histories were collected, and the patients underwent best corrected visual acuity (BCVA), fundus photography (FP), electroretinography (ERG), optical coherence tomography (OCT) and fundus autofluorescence (FAF). Venous blood was drawn from patients and family members, and genomic DNA was extracted. Next-generation sequencing of known ocular genes was applied to the proband to find pathogenic variants. Polymerase chain reaction (PCR) and Sanger sequencing were conducted for validation and segregation.Six patients from three unrelated families were enrolled. All the patients manifested decreased vision, photophobia and myopia from childhood. ERG recordings demonstrated a significant reduction in cone responses for all patients, while rod responses ranged widely from normal to moderately reduced. All patients were diagnosed with CRD, but the disease severity and progression rates in the three families were significantly different. Three pathogenic variants in theWe presented the phenotypes of three Chinese adCRD families carrying different variants at codon 838 of the

PNPLA6-related disorders include several phenotypes, such as Boucher–Neuhauser syndrome, Gordon Holmes syndrome, spastic paraplegia, photoreceptor degeneration, Oliver-McFarlane syndrome and Laurence-Moon syndrome. In this study, detailed clinical evaluations and genetic testing were performed in five (4 Chinese and 1 Caucasian/Chinese) syndromic retinal dystrophy patients. Genotype-phenotype correlations were analyzed based on review of the literatures of previously published PNPLA6-related cases. The mean age of patients and at first visit were 20.8 years (11, 12, 25, 28, 28) and 14.2 years (4, 7, 11, 24, 25), respectively. They all presented with severe chorioretinal dystrophy and profoundly decreased vision. The best corrected visual acuity (BCVA) ranged from 20/200 to 20/2000. Systemic manifestations included cerebellar ataxia, hypogonadotropic hypogonadism and hair anomalies. Six novel and three reported pathogenic variants in PNPLA6 (NM_001166111) were identified. The genotypes of the five cases are: c.3134C > T (p.Ser1045Leu) and c.3846+1G > A, c.3547C > T (p.Arg1183Trp) and c.1841+3A > G, c.3436G > A (p.Ala1146Thr) and c.2212-10A > G, c.3436G > A (p.Ala1146Thr) and c.2266C > T (p.Gln756*), c.1238_1239insC (p.Leu414Serfs*28) and c.3130A > G (p.Thr1044Ala). RT-PCR confirmed that the splicing variants indeed led to abnormal splicing. Missense variants p.Thr1044Ala, p.Ser1045Leu, p.Ala1146Thr, p.Arg1183Trp and c.3846+1G > A are located in Patatin-like phospholipase (Pat) domain. In conclusion, we report the phenotypes in five patients with PNPLA6 associated syndromic retinal dystrophy with variable systemic involvement and typical choroideremia-like fundus changes. Ocular manifestations may be the first and the only findings for years. All of our patients carried one severe deleterious variant (stop-gain or splicing variant) and one milder variant (missense variant). Retinal involvement was significantly correlated with severe deleterious variants and variants in Pat domain.

Purpose To evaluate the retinal phenotype and genetic features of Chinese patients with spinocerebellar ataxia type 7 (SCA7). Methods Detailed ophthalmic examinations, including electroretinograms, fundus photography, fundus autofluorescence and optical coherence tomography, were performed to analyse the retinal lesions of patients with SCA7. A molecular genetic analysis was completed to confirm the number of CAG repeats in ATXN7 gene on the patients and their family members. Results Eight patients from three families with SCA7 were included in this study. Trinucleotide repeat was expanded from 43 to 113 in the affected patients. The affected patients were characterised by different degrees of cone-rod dystrophy, which is positively related to the number of CAG repeats and age. All patients complained of progressive bilateral visual loss, and most cases reported visual disturbance earlier than gait movement or dysarthria. A coarse granular appearance of the macular region on scanning laser ophthalmoscopy, hypofluorescence in the macula on autofluorescence, retinal atrophy on optic coherence tomography, depression of multifocal electroretinograms and prominent abnormalities in cone-mediated responses on electrograms are the general features of SCA7-related retinopathy. Hyperreflective dots in the outer retinal layers and choroidal vessel layers are a common sign in optic coherence tomography in the advanced stage. Conclusions SCA shows a cone-rod dystrophy phenotype. The multimodal imaging of the retina is beneficial to detect the early lesions of cone-rod dystrophy related to SCA7.

Purpose To describe the functional phenotypic features of East Asian patients with RP1L1-associated occult macular dystrophy (i.e., Miyake disease). Design An international multi-center retrospective cohort study. Methods Twenty-eight participants (53 eyes) with Miyake disease were enrolled at three centres: in Japan, China, and Korea. Ophthalmological examinations including spectral-domain optic coherence tomography (SD-OCT) and multifocal electroretinogram (mfERG) were performed. Patients were classified into three functional groups based on mfERG: Group 1, paracentral dysfunction with relatively preserved central/peripheral function; Group 2, homogeneous central dysfunction with preserved peripheral function; and Group 3, widespread dysfunction over the recorded area. Three functional phenotypes were compared in clinical parameters and SD-OCT morphological classification (severe phenotype, blurred/flat ellipsoid zone and absence of the interdigitation zone; mild phenotype, preserved ellipsoid zone). Results There were eight eyes in Group 1, 40 eyes in Group 2, and five eyes in Group 3. The patients in Group 1 showed significantly later onset (P=.005) and shorter disease duration (P=.002), compared with those in Group 2. All eight eyes in Group 1 showed the mild morphological phenotype, while 43/45 eyes in Groups 2 and 3 presented the severe phenotype, which identified a significant association between the functional grouping and the morphological classification (P Conclusions A spectrum of functional phenotypes of Miyake disease was first documented with identifying three functional subtypes. Patients with paracentral dysfunction had the mildest phenotype, and those with homogeneous central or widespread dysfunction showed overlapping clinical findings with severe photoreceptor changes, suggesting various extents of visual impairment.

Lipid metabolic deficiencies are associated with many genetic disorders. Bietti crystalline dystrophy (BCD), a blindness-causing inherited disorder with changed lipid profiles, is more common in Chinese and Japanese than other populations. Our results reveal that mouse models lacking Cyp4v3 have less physiological and functional changes than those of BCD patients with this gene defect. After the administration of a high-fat diet (HFD), the occurrence of retinal lesions were both accelerated and aggregated in the Cyp4v3

Background Retinocytoma is a rare benign retinal tumor associated with variants in the RB1 gene. Ophthalmoscopic features can include a translucent retinal mass, calcification, retinal pigment epithelial alteration and chorioretinal atrophy. Methods Detailed ophthalmological examinations were performed in a Chinese patient with retinocytoma and his daughter with bilateral retinoblastoma. Sanger sequencing was performed to detect RB1 genetic variants in the patient, his daughter and tumor tissue from his daughter. Results A 33‐year‐old man presented with poor vision and strabismus in the right eye since childhood. Fundus examination revealed a round yellow‐white lesion stretching from the nasal side of the optic disc to the temporal periphery of the right eye. Sequencing result identified a reported variant (c.658C>G, p.Leu220Val) in the RB1 gene (NM_000321.2) of DNA extracted from peripheral blood of the patient and his daughter. The missense variant was also found in the tumor tissue from his daughter. Conclusions We report detailed clinical features and genetic analysis of a case with unilateral retinocytoma. Retinocytoma has a wide range of clinical phenotypes; genetic testing is therefore a useful tool for the diagnosis of atypical cases., Retinocytoma is a rare benign retinal tumor associated with variants in the RB1 gene. Retinocytoma has a wide‐range of clinical phenotypes; genetic testing is therefore a useful tool for the diagnosis of atypical cases.

Micron-sized alumina (Al2O3) short fibre and/or nano-sized alumina (Al2O3) particles were squeezed cast into Mg AM60 alloy. Two types of 7 vol.% Fibre/AM60, and (7 vol. % Fibre + 3 vol.% nano-particle)/AM60 composites, as well as the unreinforced matrix alloy were prepared. The corrosion behaviors of the composites as well as the unreinforced matrix alloy were investigated by using the potential dynamic polarization test. Compared with the matrix alloy, the introduction of micron-sized alumina fibres decreased the corrosion resistance of Mg alloy AM60 considerably due to the presence of excessive interfaces between the fibre and matrix. The high density of grain boundaries and the absence of noble precipitates such as β-Mg17Al12 phases and Al–Mn intermetallics at the grain boundaries in the composites should be for the reduction in their corrosion resistance. The addition of the nano-sized particles led to almost no further reduction in the corrosion resistance of the composite.

Static buildup model (SBM) is an analytical approach to predict upstream buildup profile of circular matrix in high-gradient magnetic separation (HGMS). But it was confined to single-wire system in idealized fluid and magnetic field, and was not applicable for more complicated or generalized systems. As better separation performance can be obtained by introducing composite force field or employing novel structural matrices in HGMS, it is necessary to develop models that are more adaptable for predicting particle buildup. In this paper, a simulation model based on SBM was developed to extend its application to complicated situation. The boundary of the buildup was updated by judging whether a particle released from locations near buildup surface would stay or not. And a characterized thickness within boundary layer was proposed to ensure that the released particles were subjected to forces of the same expression as that in SBM. The established model was proved to obtain close results with SBM when HGMS system was in idealized condition. Experimental results testified the model’s ability to predict saturated buildup profile of both circular and elliptic matrices in a realistic system. Since fluid and magnetic field information are processed by the simulation software, this model is also believed applicable for more complicated conditions such as multi-wire system and novel structure matrix system, which will be investigated in follow-up studies.

For advanced engineering design and manufacturing of light integrity magnesium automotive applications, it is critical to understand the effect of cross section thicknesses and metal pouring temperatures on mechanical properties of squeeze cast magnesium alloys. In this work, cylindrical coupons of magnesium alloy AJ62 with a diameter of 0.10 m and cross section thicknesses of 0.02 mm squeeze cast under an applied pressure of 60 MPa and with various pouring temperatures of 680, 700 and 720 °C. The results of tensile testing indicated that the mechanical properties of squeeze cast AJ62 alloy including yield strength (YS), ultimate tensile strength (UTS) and elongation (Ef) improved as the metal pouring temperatures decreased. A reduction in the pouring temperature from 720 to 680 °C increased the UTS to 179.6 from 126. 1 MPa, the YS to 144.6 from 91.4 MPa, and the ef to 3.6% from 1.3%. The mircrostruecture analyses show that the low pouring temperature were favourable for the refinement of dendriti...

Purpose: To identify pathogenic gene variants in the NOD2 gene and assess the clinical features of a cohort of Chinese patients affected with Blau syndrome.Methods: Eight patients from seven unrela...

ABCA4 gene associated retinal dystrophies (ABCA4-RD) are a group of inherited eye diseases caused by ABCA4 gene mutations, including Stargardt disease, cone-rod dystrophy and retinitis pigmentosa. With the development of next-generation sequencing (NGS), numerous clinical and genetic studies on ABCA4-RD have been performed, and the genotype and phenotype spectra have been elucidated. However, most of the studies focused on the Caucasian population and limited studies of large Chinese ABCA4-RD cohorts were reported. In this study, we summarized the phenotypic and genotypic characteristics of 129 Chinese patients with ABCA4-RD. We found a mutation spectrum of Chinese patients which is considerably different from that of the Caucasian population and identified 35 novel ABCA4 mutations. We also reported some rare and special cases, such as, pedigrees with patients in two generations, patients diagnosed with cone-rod dystrophy or retinitis pigmentosa, patients with subretinal fibrosis and patients with preserved foveal structure. At the same time, we focused on the correlation between the genotypes and phenotypes. By the comprehensive analysis of multiple clinical examinations and the application of multiple regression analysis, we proved that patients with two "null" variants had a younger onset age and reached legal blindness earlier than patients with two "none-null" variants. Patients with one or more "none-null" variants tended to have better visual acuity and presented with milder fundus autofluorescence changes and more preserved rod functions on the full-field electroretinography than patients with two "null" variants. Furthermore, most patients with the p.(Phe2188Ser) variant shared a mild phenotype with a low fundus autofluorescence signal limited to the fovea and with normal full-field electroretinography responses. Our findings expand the variant spectrum of the ABCA4 gene and enhance the knowledge of Chinese patients with ABCA4-RD.

Magnetic matrix is a key component of high gradient magnetic separation (HGMS) system. Special shape matrices have brought great attentions from researchers whereas only elliptic and circular matrices have been properly modeled and comprehensively investigated. Our previous study showed that diamond matrices present good magnetic characteristics in axial HGMS and are worthy of being comprehensively studied. In this paper, a 2D dynamic simulation model was developed to representatively describe particle capture for the 3D axial HGMS. Quantitative analysis on particle capture cross section (PCCS) revealed the matching relation between aspect ratio and magnetic induction for maximum particle capture by diamond matrix. It is found that the optimal aspect ratio decreases as magnetic induction increases, and is independent on particle size (in the size range of 1–30 μm). The advantage of favorable aspect ratio is more prominent for smaller particles under lower magnetic induction. Comparative study reveals that effect of aspect ratio on particle capture performance of diamond and elliptic matrices are quite similar, and their optimal aspect ratios are nearly identical under specific induction. Diamond matrix exhibits a slight superiority over elliptic matrix in most cases, making it a kind of promising matrix in axial HGMS. An empirical equation has been proposed to determine the optimal aspect ratio, and it is estimated that the optimal aspect ratio of elliptic and diamond matrices are about 0.75‧Ms/B0.

To compare disease severity in detail between patients carrying variants in exons 1-14 and ORF15 of retinitis pigmentosa GTPase regulator (RPGR).Systematic next-generation sequencing data analysis, Sanger sequencing validation and segregation analysis were utilised to identify the pathogenic variants. Detailed ophthalmic examinations, including electroretinograms, fundus photography, fundus autofluorescence and optical coherence tomography were performed. Statistical analysis, including age adjustment and comparison, were performed based on cross-sectional level to compare disease severity between variants in the two RPGR variant groups.Sixty-two variants were identified in RPGR in 86 patients from 77 unrelated families. Twenty-nine (37.7%) had variants in RPGR-exons 1-14 (group 1) and 48 (62.3%) in RPGR-ORF15 (group 2). Eighty-four patients were diagnosed with X-linked retinitis pigmentosa and only two patients with cone-rod dystrophy. LogMAR visual acuity increased 0.035 and 0.022 each year on average in group 1 and group 2, respectively. Group 2 patients had better visual acuity with a mean logMAR difference of 0.4378, which is significant after age adjustment (P 0.01). Neither the value of log (ellipsoid zone width) nor central retinal thickness was significantly correlated with variant grouping after considering the effect of the age variable (P = 0.56 and 0.40, respectively). Spherical refractive error did not differ significantly between the two variant groups (P = 0.17). Patterns of autofluorescence included a hyperfluorescent ring at the posterior pole, diffuse hyperfluorescence in the macular area, and dark macular autofluorescence with or without fovea hyperfluorescence. The age and proportion of fundus autofluorescence patterns between the two variant groups were significantly different (P 0.01).Patients with variants in exons 1-14 retained less visual acuity than patients with ORF15 variants and deteriorated faster. However, the ellipsoid zone widths, central retinal thickness and refractions were comparable between the two groups. Autofluorescence pattern relates to the age and the variant grouping.

High gradient magnetic separation (HGMS) is widely applied in many industrial and scientific fields. Transversal high gradient magnetic separator applied in industry has relative higher magnetic leakage due to the large magnetic pole spacing and consequently low capacity as well as low recovery of fine minerals. Optimization of transversal HGMS is of great significance for improving mineral particle efficiency or reducing energy consumption. In this study, a new concept of matching relation between matrix aspect ratio and applied magnetic induction for maximum particle capture in transversal HGMS was proposed. Effect of matrix aspect ratio on particle capture was studied under equal matrix cross-section area and equal matrix horizontal axis using extended particle capture models for saturated and unsaturated matrices as well as model selection methodology. Particle motion trajectories under different circumstances were depicted and particle capture radii were determined and compared. Results showed that there existed matching relation between matrix aspect ratio and applied magnetic induction for maximum particle capture under the two cases considered. The matching relation is independent on particle and matrix size. Particle capture radius of matrices with the optimal aspect ratio can be much larger than that of conventional rod matrices. The matching relation can be used to configure the HGMS system for improving mineral recovery or reducing energy consumption.

Longitudinal high gradient magnetic separation (HGMS) is the most widely applied in industry by virtue of to its high processing capacity and low magnetic leakage. However, due to introduction of pulsating flow and the limited magnetic forces induced by rod matrices, longitudinal high gradient magnetic separator still showed quite lower recovery compared with horizontal high intensity magnetic separator in recovering ultrafine magnetic minerals. Optimization of longitudinal HGMS system is of great significance for improving particle capture efficiency or reducing energy consumption. In this study, we proposed a new concept of matching relation between matrix aspect ratio and applied induction for maximum particle capture in longitudinal HGMS. Particle capture performance of matrices with aspect ratio of 1/5–6 in applied induction of 0.2–2T were investigated using extended particle capture models for unsaturated and saturated matrices as well as model selection methodology. The matching relation under the two cases of equal matrix cross-section area and equal horizontal axis were demonstrated. Particle motion trajectories around matrices were depicted and particle capture radius was determined. It was proved that there existed matching relation between matrix aspect ratio and applied induction for maximum particle capture for both the two cases and the relation was independent of matrix and particle size. The matching relation can be adopted to configure the HGMS system for improving particle capture efficiency or reducing energy consumption. Based on results of this study, it was also inferred that there should exist matching relation between matrix aspect ratio and applied induction for maximum separation efficiency.

Retinitis pigmentosa (RP) is an inheritable retina degenerative disease leading to blindness. Despite the identification of 70 genes associated with RP, the genetic cause of similar to 40% of RP patients remains to be elucidated. Whole-exome sequencing was applied on the probands of a RP cohort of 68 unsolved cases to identify candidate genetic mutations. A homozygous missense variant (c.173C > T, p.T58 M) was found in HKDC1 in two unrelated families presenting late-onset retinal degeneration. This variant affects highly conserved amino acid residue and is very rare in several databases and absent in 4000 ethnic-matched controls. Mutant HKDC1 protein partially lost hexokinase activity. Hkdc1 is expressed in the mouse retina and localized to photoreceptor inner segments. To elucidate the in vivo roles of Hkdc1 in the retina, we generated Hkdc1 knockout (KO) mouse models using CRISPR/Cas9 technique. Tkwo independent alleles were identified and backcrossed to C57BL/6 J for 6 generations. Absence of HKDC1 expression in the Hkdc1 KO retina was confirmed by western blot and immunostaning using HKDC1 antibody. Hkdc1 KO mice exhibited reduced scotopic electroretinogram response and thinner outer nuclear layer, similar to some of the human patient phenotypes. Loss of Hkdc1 led to mislocalization of rhodopsin to 3 the inner segments and cell bodies of rods in some regions in the retina. Taken together, our data demonstrated that HKDC1 is associated with autosomal recessively inherited RP.

Nance-Horan syndrome is a rare X-linked recessive inherited disease with clinical features including severe bilateral congenital cataracts, characteristic facial and dental abnormalities. Data from Chinese Nance-Horan syndrome patients are limited. We assessed the clinical manifestations of a Chinese Nance-Horan syndrome pedigree and identified the genetic defect. Genetic analysis showed that 3 affected males carried a novel small deletion in NHS gene, c.263_266delCGTC (p.Ala89TrpfsTer106), and 2 female carriers were heterozygous for the same variant. All 3 affected males presented with typical Nance-Horan syndrome features. One female carrier displayed lens opacities centered on the posterior Y-suture in both eyes, as well as mild dental abnormalities. We recorded the clinical features of a Chinese Nance-Horan syndrome family and broadened the spectrum of mutations in the NHS gene.

Purpose IFT81, a core component of the IFT-B complex, involved in the bidirectional transport of ciliary proteins, has been recently implicated in syndromic ciliopathies. However, none of the IFT-B core complex proteins have been associated with nonsyndromic retinal dystrophies. Given the importance of ciliary transport in photoreceptor function and structural maintenance, we sought to investigate the impact of IFT (intraflagellar transport) mutations in nonsyndromic retinopathies. Methods Whole exome sequencing was performed on 50 cone-rod dystrophy (CRD) patients that were previously screened for mutations in known retinal disease genes. The impact of candidate mutation was studied using in vitro cell system and in vivo zebrafish assay to determine the pathogenicity of the variant. Results Compound heterozygous mutations in IFT81, including one nonsense (c.1213C>T, p.R405*) and one missense variant (c.1841T>C, p.L614P), were identified in a nonsyndromic CRD proband. Extensive functional analyses of the missense variant in cell culture and zebrafish strongly suggests its pathogenic nature. Loss of IFT81 impairs ciliogenesis and, interestingly, the missense variant displayed significantly reduced rescue of ciliogenesis in the IFT81 knockdown in vitro system. Consistently, dramatic reduction of rescue efficiency of the ift81 mutant zebrafish embryo by mRNA with the missense variant was observed, further supporting its pathogenicity. Conclusions Consistent with the function of the IFT-B complex in the maintenance of photoreceptor cilium, we report a case of mutations in a core IFT-B protein, IFT81. This represents the first report of mutations in IFT81 as a candidate gene for nonsyndromic retinal dystrophy, hence expanding the phenotype spectrum of IFT-B components.

X-linked ocular albinism (OA1) is an X-linked inherited disease characterized by hypopigmentation of the fundus and nystagmus. Our study performed mutation analysis of the G protein-coupled receptor 143 gene (GPR143) and assessed the clinical characteristics of OA1 in three Chinese families. Three novel mutations, c.333_360+14del42insCTT, c.276G>A (p.W92X), and c.793C>T (p.R265X), were identified in GPR143 by PCR followed by Sanger sequencing in these families. All affected individuals presented with nystagmus, photophobia, poor visual acuity, foveal hypoplasia and varying degrees of hypopigmentation of the fundus. The fundus of female carriers showed pigmented streaks alternating with hypopigmented streaks. These results allowed us to expand the spectrum of mutations in GPR143 and phenotypes associated with ocular albinism.

Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

AimsTo investigate the prevalence, ethnic differences and associated risk factors for pterygium in Han and Manchu populations aged 40–79 years in Hebei province, China.DesignCross-sectional study, as a part of the China National Health Survey.SettingHebei province, China.ParticipantsA multistage cluster sampling method with urbanisation level-based stratification was used to select participants for this study. A total of 4591 individuals over 40 years were recruited for this study. Inclusive criteria: (1) residents who had been living in Hebei for more than 1 year; (2) Han individuals with both parents being Han, or Manchu individuals with both parents being Manchu; (3) underwent ophthalmic examinations and (4) information in the questionnaire was complete.Main outcome measuresMultiple logistic regression analysis was used to evaluate the association between pterygium prevalence and factors of interest.ResultsA total of 3790 individuals (2351 Hans and 1439 Manchus) met the study criteria, of which 248 were diagnosed with pterygium (6.5%). There was no significant difference between the prevalence rates in Hans (6.2%) and Manchus (7.2%) (p=0.232). Multivariate analysis revealed that the risk factors for grade 2 or higher pterygium were increasing age (pConclusionThe overall prevalence of pterygium in Han and Manchu population in Hebei, China was approximately 6.1%. There were no differences in the prevalence of pterygium between Hans and Manchus, and the race was not a risk factor. This is the first study to report on the positive association between premature menopause and pterygium in females and between higher HDL levels and pterygium in males.