To reveal the characteristics of ocular changes in patients with biallelic CRB1 mutations.
Comparative exome sequencing and retrospective case series on clinical data.
Seventy-four patients from 63 ...families with biallelic potential pathogenic variants in CRB1 were selected from our in-house exome sequencing. The clinical data were reviewed and evaluated in detail, including best-corrected visual acuity, fundus photography, optical coherence tomography (OCT), and electroretinogram (ERG).
Biallelic CRB1 variants, involving 45 variants including 23 novel, were identified in 40 novel families based on exome sequencing. Analyzing clinical data of the 74 individuals from 63 families revealed the following CRB1-associated phenotypes: (1) early-onset reduced visual acuity with congenital nystagmus; (2) 2 types of characteristic retinal changes including yellowish geographic macular degeneration (YMD) or nummular pigment deposits (NPD) at posterior retina with bone-spicule pigmentation at midperipheral retina; (3) undetectable rod and cone responses on ERG; (4) cystoid macular edema or macular atrophy on OCT. YMD and NPD are unique and CRB1-associated. Long-term follow-up examination as well as age- and variant-dependent phenotypic analysis suggested YMD is the early fundus change that would gradually progress to NPD.
YMD and NPD are 2 major characteristic CRB1-associated fundus changes and the former one will advance to the latter with age. Recognizing such characteristic signs associated with biallelic CRB1 variants may be of value in areas without widespread access to genetic testing where a more targeted approach is needed and might be biomarkers for evaluation of effects for future intervention.
•Two types of CRB1-associated fundus changes were identified.•The progression of CRB1-characteristic fundus changes with age were found.•The correlations between the signature fundus of CRB1 and other CRB1-associated phenotypes were revealed.•The genotype-phenotype association of CRB1 variants was explored.
The aim of this study was to investigate the mutation spectrum and frequency of 34 known genes in 18 Chinese families with congenital cataracts.
Genomic DNA and clinical data was collected from 18 ...families with congenital cataracts. Variations in 34 cataract-associated genes were screened by whole exome sequencing and then validated by Sanger sequencing.
Eleven candidate variants in seven of the 34 genes were detected by exome sequencing and then confirmed by Sanger sequencing, including two variants predicted to be benign and the other pathogenic mutations. The nine mutations were present in 9 of the 18 (50%) families with congenital cataracts. Of the four families with mutations in the X-linked NHS gene, no other abnormalities were recorded except for cataract, in which a pseudo-dominant inheritance form was suggested, as female carriers also had different forms of cataracts.
This study expands the mutation spectrum and frequency of genes responsible for congenital cataract. Mutation in NHS is a common cause of nonsyndromic congenital cataract with pseudo-autosomal dominant inheritance. Combined with our previous studies, a genetic basis could be identified in 67.6% of families with congenital cataracts in our case series, in which mutations in genes encoding crystallins, genes encoding connexins, and NHS are responsible for 29.4%, 14.7%, and 11.8% of families, respectively. Our results suggest that mutations in NHS are the common cause of congenital cataract, both syndromic and nonsyndromic.
Purpose
The pathogenic variants in
TSPAN12
could lead to familial exudative vitreoretinopathy (FEVR), which has high clinical variability. This study aims to assess the pathogenicity of
TSPAN12
...variants and their phenotypic spectrum based on exome sequencing from 7092 probands with different eye conditions.
Methods
The variants in
TSPAN12
were selected from exome sequencing data of samples from 7092 probands with different forms of eye conditions. Potentially pathogenic variants were evaluated through the annotation of types, locations, population frequencies, and in silico predictions of variants from in-house data, gnomAD, and published literature. The clinical features of patients with potentially pathogenic variants in
TSPAN12
were assessed.
Results
A total of 45 variants in
TSPAN12
with coding effects were detected based on the exome data from 7092 probands, among which 31 were classified as pathogenic variants including 15 novels. The 31 variants were identified in 34 probands with various initial diagnoses, including FEVR in 21 probands and diseases other than FEVR in the remaining 13 probands. Biallelic pathogenic variants were identified in one proband with initial diagnosis of high myopia.
Conclusion
Truncating variants and the missense variants that are predicted as deleterious are likely pathogenic variants of
TSPAN12
. Approximately 61.8% of patients with pathogenic variants in this gene had an initial diagnosis of FEVR, and the remaining 38.2% of patients had various initial diagnoses. These findings expand the understanding about variant evaluation of
TSPAN12
and phenotypic spectrum of
TSPAN12
-associated FEVR.
Despite the advent of genomic sequencing, molecular diagnosis remains unsolved in approximately half of patients with Mendelian disorders, largely due to unclarified functions of noncoding regions ...and the difficulty in identifying complex structural variations. In this study, we map a unique form of central iris hypoplasia in a large family to 6q15-q23.3 and 18p11.31-q12.1 using a genome-wide linkage scan. Long-read sequencing reveals a balanced translocation t(6;18)(q22.31;p11.22) with intergenic breakpoints. By performing Hi-C on induced pluripotent stem cells from a patient, we identify two chromatin topologically associating domains spanning across the breakpoints. These alterations lead the ectopic chromatin interactions between APCDD1 on chromosome 18 and enhancers on chromosome 6, resulting in upregulation of APCDD1. Notably, APCDD1 is specifically localized in the iris of human eyes. Our findings demonstrate that noncoding structural variations can lead to Mendelian diseases by disrupting the 3D genome structure and resulting in altered gene expression.Here, the authors identify a form of central iris hypoplasia affecting the pupillary zone. They suggest that noncoding structural variations can lead to Mendelian diseases by disrupting the 3D genome structure and resulting in altered gene expression.
The new Modified-690Gd alloy, namely as Ni–30Cr-(10-x) Fe-xGd (x = 0.5, 1.0, 1.5,2.0, 3.0 wt%) for function structure integrated thermal neutron shielding has been prepared and characterized. The ...Modified-690Gd alloy was mainly composed of γ austenite matrix and (Ni, Cr, Fe)5Gd precipitated along grain boundaries. The new Modified-690Gd alloy had great mechanical properties, which had the tensile strength exceeding 620 MPa and the elongation being above 50%. Meanwhile, this alloy had excellent weldability and good corrosion resistance in boric acid. The new Modified-690Gd alloy is expected to be a kind of high efficiency thermal neutron shielding materials.
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Unilateral high myopia (uHM), commonly observed in patients with retinal diseases or only with high myopia, is frequently associated with amblyopia with poor prognosis. This study aims to reveal the ...clinical and genetic spectrum of uHM in a large Chinese cohort.
A total of 75 probands with simplex uHM were included in our Pediatric and Genetic Eye Clinic. Patients with significant posterior anomalies other than myopic fundus changes were excluded. Variants were detected by exome sequencing and then analyzed through multiple-step bioinformatic and co-segregation analysis and finally confirmed by Sanger sequencing. Genetic findings were correlated with associated clinical data for analysis.
Among the 75 probands with a mean age of 6.21 ± 4.70 years at the presentation, myopic fundus of C1 and C2 was observed in 73 (97.3%) probands. Surprisingly, specific peripheral changes were identified in 63 eyes involving 36 (48.0%) probands after extensive examination, including peripheral retinal avascular zone (74.6%, 47/63 eyes), neovascularization (54.0%), fluorescein leakage (31.7%), peripheral pigmentary changes (31.7%), and others. Exome sequencing identified 21 potential pathogenic variants of 13 genes in 20 of 75 (26.7%) probands, including genes for Stickler syndrome (COL11A1 and COL2A1; 6/20), FEVR (FZD4, LRP5, and TSPAN12; 5/20), and others (FBN1, GPR179, ZEB2, PAX6, GPR143, OPN1LW, FRMD7, and CACNA1F; 9/20). For the peripheral retinal changes in the 20 probands, variants in Stickler syndrome-related genes were predominantly associated with retinal pigmentary changes, lattice degeneration, and retinal avascular region, while variants in genes related to FEVR were mainly associated with the avascular zone, neovascularization, and fluorescein leakage.
Genetic defects were identified in about one-fourth of simplex uHM patients in which significant consequences may be hidden under a classic myopic fundus in up to half. To our knowledge, this is the first systematic genetic study on simplex uHM to date. In addition to routine care of strabismus and amblyopia, careful examination of the peripheral retina and genetic screening is warranted for patients with uHM in order to identify signs of risk for retinal detachment and other complications and provide meaningful genetic counseling.
Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA), the most common forms of hereditary optic neuropathy, are easily confused, and it is difficult to distinguish one from the ...other in the clinic, especially in young children. The present study was designed to survey the mutation spectrum of common pathogenic genes (OPA1, OPA3 and mtDNA genes) and to analyze the genotype-phenotype characteristics of Chinese patients with suspected childhood-onset hereditary optic neuropathy. Genomic DNA and clinical data were collected from 304 unrelated Chinese probands with suspected hereditary optic neuropathy with an age of onset below 14 years. Sanger sequencing was used to screen variants in the coding and adjacent regions of OPA1, OPA3 and the three primary LHON-related mutation sites in mitochondrial DNA (mtDNA) (m.3460G>A, m.11778G>A and m.14484T>C). All patients underwent a complete ophthalmic examination and were compared with age-matched controls. We identified 89/304 (29.3%) primary mtDNA mutations related to LHON in 304 probands, including 76 mutations at m.11778 (76/89, 85.4% of all mtDNA mutations), four at m.3460 (4/89, 4.5%) and nine at m.14484 (9/89, 10.1%). This result was similar to the mutation frequency among Chinese patients with LHON of any age. Screening of OPA1 revealed 23 pathogenic variants, including 11 novel and 12 known pathogenic mutations. This study expanded the OPA1 mutation spectrum, and our results showed that OPA1 mutation is another common cause of childhood-onset hereditary optic neuropathy in Chinese pediatric patients, especially those with disease onset during preschool age.
Corneal dystrophies (CDs) represent a group of inherited diseases characterized by the progressive deposit of abnormal materials in the cornea. This study aimed to describe the variant landscape of ...15 genes responsible for CDs based on a cohort of Chinese families and a comparative analysis of literature reports. Families with CDs were recruited from our eye clinic. Their genomic DNA was analyzed using exome sequencing. The detected variants were filtered using multi-step bioinformatics and confirmed using Sanger sequencing. Previously reported variants in the literature were summarized and evaluated based on the gnomAD database and in-house exome data. In 30 of 37 families with CDs, 17 pathogenic or likely pathogenic variants were detected in 4 of the 15 genes, including
,
,
, and
. A comparative analysis of large datasets revealed that 12 of the 586 reported variants are unlikely causative of CDs in monogenic mode, accounting for 61 of 2933 families in the literature. Of the 15 genes, the gene most frequently implicated in CDs was
(1823/2902, 62.82% of families), followed by
(483/2902, 16.64%) and
(201/2902, 6.93%). This study presents, for the first time, the landscape of pathogenic and likely pathogenic variants in the 15 genes responsible for CDs. Awareness of frequently misinterpreted variants, such as c.1501C>A, p.(Pro501Thr) in
, is crucial in the era of genomic medicine.
is the most common cause of X-linked retinitis pigmentosa (RP), of which female carriers are also frequently affected. The aim of the current study was to explore the
variation spectrum and ...associated phenotype based on the data from our lab and previous studies.
Variants in
were selected from exome sequencing data of 7,092 probands with different eye conditions. The probands and their available family members underwent comprehensive ocular examinations. Similar data were collected from previous reports through searches in PubMed, Web of Science, and Google Scholar. Systematic analyses of genotypes, phenotypes and their correlations were performed.
A total of 46 likely pathogenic variants, including nine missense and one in-frame variants in RCC1-like domain and 36 truncation variants, in
were detected in 62 unrelated families in our in-house cohort. In addition, a total of 585 variants, including 491 (83.9%) truncation variants, were identified from the literature. Systematic analysis of variants from our in-house dataset, literature, and gnomAD suggested that most of the pathogenic variants of
were truncation variants while pathogenic missense and in-frame variants were enriched in the RCC1-like domain. Phenotypic variations were present between males and female carriers, including more severe refractive error but better best corrected visual acuity (BCVA) in female carriers than those in males. The male patients showed a significant reduction of BCVA with increase of age and males with exon1-14 variants presented a better BCVA than those with ORF15 variants. For female carriers, the BCVA also showed significant reduction with increase of age, but BCVA in females with exon1-14 variants was not significant difference compared with those with ORF15 variants.
Most pathogenic variants of
are truncations. Missense and in-frame variants located outside of the RCC1-like domain might be benign and the pathogenicity criteria for these variants should be considered with greater caution. The BCVA and refractive error are different between males and female carriers. Increase of age and location of variants in ORF15 contribute to the reduction of BCVA in males. These results are valuable for understanding genotypes and phenotypes of
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