Best vitelliform macular dystrophy (BVMD), caused by pathogenic variants of the BEST1 gene, has not been reported in association with cataracts and ocular malformations. We reported a case with a ...complex ocular phenotype comprising microphthalmia, microcornea, cataract, and vitelliform macular dystrophy.
A six-year-old girl manifested photophobia and a poor visual behavior. A thorough ophthalmic examination revealed the patient to have bilateral microphthalmia, microcornea, congenital cataract, and Best vitelliform macular dystrophy (BVMD). Whole exome sequencing (WES) identified one variant in the BEST1 and one variant in CRYBB2 genes: c.218 T > G p.(Ile73Arg) and c.479G > C p.(Arg160Pro). The first variant was inherited from the proband's father, who was diagnosed with subclinical BVMD, while the second was a de novo variant. A minigene assay showed that c.218 T > G in BEST1 did not affect pre-mRNA splicing.
This case suggests that the complex ocular phenotype comprising BVMD and congenital cataract with microphthalmia cannot be explained by variation in one gene but is caused by variants in BEST1 and CRYBB2. This case highlights the importance of general clinical evaluation and comprehensive genetic testing for diagnosing complex eye diseases.
Leber congenital amaurosis (LCA) and early onset severe retinal dystrophy (EOSRD) are clinically and genetically heterogeneous inherited retinal disorders that cause severe visual impairment in ...children. The objective of this study was to describe the mutation profile and phenotypic characteristics in Chinese patients with LCA or EOSRD.
Retrospective consecutive case series (2010-2017) study was performed in 148 probands (91 with LCA and 57 with EOSRD). All patients underwent ophthalmic evaluation. Mutations were revealed using targeted next-generation sequencing, followed by Sanger DNA-sequencing and real-time quantitative PCR analysis.
We identified two diseasing-causing mutations in 88 unrelated patients, heterozygous autosomal dominant mutations in 11 probands and X-linked hemizygous mutations in 11 patients, for an overall mutation detection rate of 74.3% (110/148). We detected 158 different disease-causing mutations involving 14 LCA genes, 16 retinitis pigmentosa or cone-rod dystrophy genes and 3 syndromic retinal dystrophy genes. Of these 158 mutations, 98 were novel. The most common mutation was p.Q141X of
, with a gene-specific allele frequency of 60%. The first five most frequently mutated genes were
(11.0%),
(8.8%) and
,
and
(each 7.7%) in the patients with LCA and
(12.3%),
(10.5%),
(10.5%),
(7.0%) and
(5.3%) in the patients with EOSRD.
Our results revealed that the mutation spectrum of patients with LCA differs from that of the patients with EOSRD and established the configuration of the mutation frequencies for each LCA gene in Chinese patients, thereby providing essential information for future genetic counselling and gene therapy.
Usher syndrome (USH) refers to a group of autosomal recessive disorders causing deafness and blindness. The objectives of this study were to determine the mutation spectrum in a cohort of Chinese ...patients with USH and to describe the clinical features of the patients with mutations.
A total of 119 probands who were clinically diagnosed with USH were recruited for genetic analysis. All probands underwent ophthalmic examinations. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger-DNA sequencing, and multiplex ligation probe amplification assay, was used to detect mutations.
We found biallelic mutations in 92 probands (77.3%), monoallelic mutations in 5 patients (4.2%), and 1 hemizygous mutation in 1 patient (0.8%), resulting in an overall mutation detection rate of 78.2%. Overall, 132 distinct disease-causing mutations involving seven USH (ABHD12, CDH23, GPR98, MYO7A, PCDH15, USH1C, and USH2A) genes; 5 other retinal degeneration genes (CHM, CNGA1, EYS, PDE6B, and TULP1); and 1 nonsyndromic hearing loss gene (MYO15A) were identified, and 78 were novel. Mutations of MYOA7 were responsible for 60% of USH1 families, followed by PCDH15 (20%) and USH1C (10%). Mutations of USH2A accounted for 67.7% of USH2 families, and mutation c.8559-2A>G was the most frequent one, accounting for 19.1% of the identified USH2A alleles.
Our results confirm that the mutation spectrum for each USH gene in Chinese patients differs from those of other populations. The formation of the mutation profile for the Chinese population will enable a precise genetic diagnosis for USH patients in the future.
Mutations in the BEST1 gene can cause Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB). The aim of the current study was to establish the BEST1 mutation ...spectrum in Chinese patients with BVMD and ARB and to describe the phenotypic characteristics of patients carrying BEST1 mutations.
A total of 37 probands with a clinical diagnosis of BVMD (17 patients) or ARB (20 patients) were recruited for genetic analysis; of these, only 5 probands had a family history. All probands underwent detailed ophthalmic examinations. All coding exons and exon-intron boundaries of the BEST1 gene were screened by PCR-based DNA sequencing. In silico programs were used to analyze the pathogenicity of all the variants. Genomic DNA rearrangements of the BEST1 gene were identified by real-time quantitative PCR (RQ-PCR).
For patients with BVMD, single heterozygous BEST1 mutations were identified in 13 patients and compound heterozygous mutations were found in 3 patients. For patients with ARB, biallelic mutations were found in 13 probands and single mutant alleles in six patients. Overall, 36 disease-causing variants (20 novel mutations) of the BEST1 gene were identified, including 28 (77.8%) missense, 3 (8.3%) nonsense, 4 (11.1%) splicing effect, and 1 (2.8%) frameshift small duplication mutations.
The mutation spectrum of the BEST1 gene in Chinese patients differed from those of Caucasian patients. Mutations that cause ARB differ from those that cause BVMD. BEST1 screening is important for precise diagnosis of BVMD or ARB.
Bardet-Biedl syndrome (BBS) is a rare multisystem ciliopathy. The aim of this study was to describe the clinical and genetic features of a cohort of Chinese patients carrying biallelic BBS gene ...variants.
We recruited 34 patients from 31 unrelated pedigrees who carried biallelic pathogenic variants in BBS genes. All patients underwent ophthalmic and systematic evaluations, as well as comprehensive molecular genetic analyses. Ultimately, 14 patients were followed up over time.
We identified 47 diseasing-causing variants in 10 BBS genes; 33 were novel. Diagnosis of BBS and non-syndromic retinitis pigmentosa (RP) were established in 28 patients from 27 pedigrees and 6 patients, respectively. The two most prevalent genes in patients with BBS were BBS2 and BBS4, accounting for 51.8% of the probands. The patients exhibited clinical heterogeneity, from patients with all six primary clinical components to patients suffering from non-syndromic RP. The common components were retinal dystrophy, polydactyly, and obesity, with frequencies of 78.6% to 100%, while renal anomaly frequencies were only 7.1%. Patients exhibited early and severe visual defects and retinal degeneration. Patients with biallelic missense variants in BBS2 suffered fewer clinical symptoms and mild visual impairment. Patients with BBS10 variants tended to have cone dystrophy.
Our study defined the mutated gene profiles and established the configuration of the variation frequencies for each BBS gene in Chinese patients. Overall, our patients showed early and severe visual defects and retinal degeneration. Genetic analysis is therefore crucial for diagnosis, genetic counseling, and future gene therapy in these patients.
Choroideremia (CHM) is an X-linked chorioretinal dystrophy caused by variants in the CHM gene. The aim of this study was to report the clinical and genetic features of a cohort of affected males with ...CHM and establish the relationship between best correct visual acuity (BCVA) and age.
Twenty-seven patients from 24 unrelated families underwent detailed ophthalmic examinations and comprehensive molecular genetic analysis. We combined the 27 patients in our own cohort with 68 Chinese patients from six previously reported studies to determine a transition age for BCVA rapid decline in 95 patients.
Twenty-three causal (9 novel) CHM variants were identified in the 27 patients, who had a mean age of 30.5 ± 17.4 years and a mean BCVA (LogMAR) of 0.61 ± 0.79. Patients at different disease stages showed different extents of retinal pigment epithelium (RPE) and choroid abnormalities. Central retinal optical coherence tomography (OCT) scanning revealed defects in the ellipsoid zone and RPE in all patients and outer retinal tubulations in 75%. The 95 patients had a mean age of 33.27 ± 16.27 years and an average (LogMAR) of 0.72 ± 0.82. The BCVA did not decline rapidly before age 25, but decreased at a mean rate of 0.037logMAR/year after that age.
Our results indicated Chinese patients with CHM variants have a younger transition age for rapid BCVA decline than previously reported for other ethnic groups. Central retinal OCT scanning can identify different abnormalities in the retinal structures, and these might be used as other parameters for monitoring disease progression in patients with CHM.
X-linked retinoschisis (XLRS) is an early-onset retinal degenerative disorder caused by mutations in the
gene. The objective of this study was to describe the clinical and genetic findings in 90 ...unrelated Chinese patients with XLRS.
All patients underwent clinical examination, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, and spectral domain-optical coherence tomography (SD-OCT). A combination of molecular screening methods, including Sanger-DNA sequencing of
and targeted next-generation sequencing (TES), were used to detect mutations. In silico programs were used to analyze the pathogenicity of all the variants. Long-range PCR with subsequent DNA sequencing was employed to find the breakpoints of large deletions.
The 90 probands (mean age 17.29±12.94 years; 3-52 years) showed a variety of clinical phenotypes, and their average best correct visual acuity was 0.81±0.48 (logarithm of the minimal angle of resolution, 0-3). Of the 175 eyes analyzed, 140 (80%) had macular retinoschisis, 84 (48%) had peripheral retinoschisis, 28 (16%) had macular atrophy, and five (3%) had a normal macular structure. We identified 68 mutations in this cohort of patients, including 15 novel mutations. Most mutations (65%) were missense; the remaining null mutations included nonsense, splicing effect, frameshift indel, and large genomic DNA deletions. The 62 patients with missense mutations seemed to have relatively milder visual defects than the 28 patients with null mutations.
Patients with
mutations present profound phenotypic variability and show no clear genotype-phenotype correlations. Patients with null mutations tend to have more severe XLRS-related visual defects.
PurposeTo describe the genetic landscape of BEST1 for a large Chinese cohort with autosomal recessive bestrophinopathy (ARB), identify the missing heritability, and report a common Chinese founder ...variant. MethodsWe recruited 65 patients from 63 families with a clinical diagnosis of ARB. All patients underwent ophthalmic examinations and comprehensive genetic analyses, including Sanger DNA sequencing of BEST1 and whole genome sequencing (WGS). The effects of deep intronic variants (DIVs) on splicing were assessed using in vitro splicing assays in HEK293T cells and patient-derived peripheral blood mononuclear cells. Haplotype mapping was performed for 17 unrelated patients harboring variant c.867+97G>A. ResultsWe identified 54 distinct disease-causing variants of BEST1 in 63 pedigrees, 62 probands with biallelic variants, and one family with monoallelic variants. Sanger DNA sequencing of BEST1 initially detected 51 variants in 61 pedigrees, including 19 probands with one heterozygous variant. Subsequent WGS, combined with supplementary Sanger sequencing, revealed three missing DIVs (c.1101-491A>G, c.867+97G>A, and c.867+97G>T) in 20 families. The novel DIV c.1101-491A>G caused an abnormal splicing resulting in a 204-nt pseudoexon (PE) insertion, whereas c.867+97G>A/T relatively strengthened an alternative donor site, resulting in a 203-nt intron retention (IR). The PE and IR generated a premature termination codon downstream. Haplotype analysis identified c.867+97G>A as a common founder variant with an allele frequency of 16%. ConclusionsOur results expand the pathogenic variant spectrum of BEST1, and DIVs can explain almost all of the missing heritability. The c.867+97G>A DIV is a common founder variant for Chinese patients with ARB.
Vibrio parahaemolyticus is a food-borne pathogen that poses a serious threat to seafood safety and human health. An efficient, nontoxic, and sustainable disinfection material with a stable structure ...is urgently needed. Herein, silver (Ag)-hydroxyapatite (HAP) composite catalysts were prepared using HAP derived from waste fish bones. The Ag2.50%-HAP showed a 100% disinfection rate against V. parahaemolyticus, disinfecting nearly 7.0 lg CFU mL−1 within 15 min at a low concentration of 300 μg mL−1. This efficient disinfection activity could be attributed to the double-synergistic effect of Ag and superoxide radicals, which resulted in the destruction of bacterial cell structures and the leakage of intracellular proteins. Importantly, the composite also exhibited high activity in controlling the growth of pathogens during the storage process of Penaeus vannamei. These findings provided sustainable composite catalysts for disinfecting V. parahaemolyticus in seafood and a high-value utilization strategy for waste fish bones.
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•Hydroxyapatite (HAP) was derived from waste fish bones by a facile calcination method.•The disinfection ability of Ag-HAP against Vibrio Parahaemolyticus was studied.•The potential double-synergistic disinfection mechanism of Ag-HAP was proposed.•Ag-HAP could delay the spoilage of Penaeus vannamei.
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