To investigate the frequency of
mutation and the clinical and genetic differences between Usher syndrome type II (USH2) and retinitis pigmentosa (RP) in a large cohort of Chinese patients.
A total of ...1381 patients with inherited retinal disease (IRD) were recruited. The phenotypic and genotypic information of patients with
mutations was evaluated.
The prevalence of patients with
mutations was 15.75%, which was the most frequently detected gene in this cohort of patients. Hotspot of
mutations was c.8559-2A >G and c.2802T >G. Patients with USH2 had an earlier and more serious decline of visual function and damage to retina structure than did patients with RP in the first 10 years (p<0.05), but there was no difference in the visual prognosis between the two groups when the course of disease exceeded 10 years (p>0.05). Missense variants had less severe consequences and were found more commonly in RP, whereas more deleterious genotypes were associated with an earlier onset of disease and were found more commonly in USH2.
This study provides detailed clinical-genetic assessment of patients with
mutations of Chinese origin, enabling precise genetic diagnoses, better management of these patients and putative therapeutic approaches.
Heimler syndrome (HS) is a rare hereditary systemic disorder, partial clinically overlapping with Usher syndrome. So far, our knowledge of HS is very limited, many cases are misdiagnosed or may not ...even be diagnosed at all. This study aimed to analyze the clinical and genetic characteristics of HS, and to evaluate potential phenotype-genotype correlations.
Two HS cases caused by PEX1 mutations were identified, and a novel likely pathogenic mutation, PEX1 c.895_896insTATA, was found. The main ophthalmic finding of the two patients was consistent with retinitis pigmentosa accompanied by cystoid macular edema, but short axial length and hyperopia were also observed as two previously unreported ocular phenotypes. Analysis of the literature showed that of the 29 HS patients previously reported, 12 had PEX6 mutations, 10 had PEX1 mutations, two had PEX26 mutations, and the remaining patients were not genetically tested. Three novel genotype-phenotype correlations were revealed from analysis of these patients. First, most genotypes of every HS patient include at least one missense variant; second, at least one mutation in PEX1 or PEX6 gene affects the AAA-ATPase region in every HS patient with retinal dystrophy, suggesting AAA-ATPase region is a hypermutable region in patients with a retinal dystrophy; third, there are no significant differences between PEX1-, PEX6-, and PEX26-associated phenotypes.
Next-generation sequencing is important for the diagnosis of HS. This study expands the clinical and genetic spectrum of HS, and provides additional insights into genotype-phenotype correlations, which is vital for accurate clinical practice, genetic counseling, and pathogenesis studies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose
To provides the clinical and genetic characteristics of a series of Chinese patients with X‐linked juvenile retinoschisis (XLRS) through multimodal imaging and next‐generation sequencing.
...Methods
Thirty patients (60 eyes) from 29 unrelated families of Chinese origin with XLRS were screened using multigene panel testing, and underwent a complete clinical evaluation. All variants identified in this study and reported in the Human Gene Mutation Database were analysed.
Results
Twenty‐five distinct variants in the retinoschisin gene were identified, of which eight were novel, and one was de novo. Missense mutations were the most prevalent type, and mutation hot spot was localized in the discoidin domain. The mean Snellen best‐corrected visual acuity was 0.28 ± 0.17. Of all eyes presenting with schisis, 92.86% had lamellar schisis and 62.5% had peripheral schisis. Schisis changes mostly involved inner and outer nuclear layers. X‐linked juvenile retinoschisis (XLRS) patients had a high incidence of complications, and peripheral schisis was a risk factor for it. No obvious genotype–phenotype association was observed.
Conclusion
This study provides comprehensive analyses of the genetic and clinical characteristics of XLRS in a cohort of Chinese patients. The fourth de novo mutation in RS1 was identified. And we show that XLRS has a wide spectrum of clinical characteristics; hence, molecular diagnosis is crucial for its diagnosis, differential diagnosis and genetic counselling. Peripheral schisis is a risk factor for the high incidence of complications, and no clear genotype–phenotype correlations were found.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Bestrophin-1 (
) gene is associated with a wide range of ocular phenotypes, collectively termed as bestrophinopathy. The aim of the current study was to identify the mutation spectrum of
in a large ...cohort of Chinese patients with bestrophinopathy.
Patients clinically suspected of bestrophinopathy were screened using multigene panel testing. All
variants were confirmed by Sanger sequencing, and validated in the families.
A total of 92 patients (Best vitelliform macular dystrophy (BVMD)=77; autosomal recessive bestrophinopathy (ARB)=15) from 58 unrelated families of Chinese origin and their available family members (n=65) were recruited. Overall, 39 distinct disease-causing
variants were identified, including 13 novel variants, and two reported variants but novel for ARB. Of them, 14 were associated with ARB, 23 with BVMD and two (c.604C>T and c.898G>A) with both BVMD and ARB. Most mutations associated with BVMD were missense (97.78%), while ARB was associated with more complex mutations, including missense (88.46%), splicing effect (3.85%), and frameshifts (15.38%).
hotspots were c.898G>A and c.584C>T among BVMD and ARB patients, respectively. Hot regions were located in exons 8, 2 and 6 in BVMD patients, and in exons 5 and 7 in ARB patients. The overall penetrance of
in our cohort was 71.30%, no de novo mutations were identified.
This is the largest study to date that provides major population-based data of the
mutation spectrum in China. Our results can serve as a well-founded reference for genetic counselling for patients with bestrophinopathy of Chinese origin.
The peripheral benzodiazepine receptor (TSPO/PBR) is highly conserved among different species but with perplexing biochemical functions. Multiple ligands of TSPO show commendable regulatory ...activities in lots of biological functions, such as neuro‐protection, cholesterol transport, and so on. These researches support that TSPO may be a potential target for disease treatment and drug development. Previous studies have shown that its ligands benzodiazepines show a satisfactory effect on melanogenic promotion. However, the potential application of TSPO in drug development for pigmentary disorder needs further investigation. In this study, we confirmed the melanogenesis induction of TSPO ligand, Ro5‐4864 in mouse melanoma cell lines, human skin tissue, and zebrafish embryos by inducing melanin synthesis and melanosome transport. Molecular genetics and pharmacological studies showed that TSPO deficiency did not affect melanin production in B16F10 cells and zebrafish embryos, nor did it affect the melanin promotion effect of Ro5‐4864. Whether or not TSPO exists, the expression of lots of melanogenesis‐related proteins, such as TYR, TRP‐1, DCT, Mlph, and Rab27 was upregulated with the Ro5‐4864 administration. These results indicated that Ro5‐4864 induces melanogenesis in a TSPO‐independent manner, which is inconsistent with previous research. This research is a reminder that we need to be very careful during target validation in drug development.
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To identify the mutational spectrum in a Chinese cohort with congenital cataracts.
Probands (n = 164) with congenital cataracts and their affected or unaffected available family members were ...recruited for clinical examinations and panel-based next-generation sequencing, then classified into a cohort for further mutational analysis.
After recruitment (n = 442; 228 males and 214 females), 49.32% (218/442) of subjects received a clinical diagnosis of congenital cataracts, and 56.88% (124/218) of patients received a molecular diagnosis. Eighty-four distinct variants distributed among 43 different genes, including 42 previously reported variants and 42 novel variants, were detected, and 49 gene variants were causally associated with patient phenotypes; 27.37% of variants (23/84) were commonly detected in PAX6, GJA8 and CRYGD, and the three genes covered 33.06% of cases (41/124) with molecular diagnosis. The majority of genes were classified as genes involved in nonsyndromic congenital cataracts (19/43, 44.19%) and were responsible for 56.45% of cases (70/124). The majority of functional and nucleotide changes were missense variants (53/84, 63.10%) and substitution variants (74/84, 88.10%), respectively. Nine de novo variants were identified.
This study provides a reference for individualized genetic counseling and further extends the mutational spectrum of congenital cataracts.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose
To explore an early, rapid and precise diagnosis of Stickler syndrome type I (STL1) and to enrich the spectrum of COL2A1 mutations in the Chinese population, which is poorly studied at ...present.
Methods
In the current study, we analysed 115 patients with high myopia by next‐generation sequencing and identified five STL1 patients from four unrelated Chinese families. The clinical features of all patients were reviewed in detail.
Results
Four variants of COL2A1 were identified, including two novel variants (c.1435delG and c.184delG) and two previously reported variants (c.1221+1G>A and c.1030C>T). Three variants caused premature termination codons which were common in STL1. In addition, we proposed a new diagnostic tactic to improve early diagnostics of STL1 in patients.
Conclusion
In this study, our findings expanded the spectrum of COL2A1 mutations with two novel variants and provided a new diagnostic tactic for reference, which was of great significance. Precise diagnosis on the basis of clinical manifestations and genetic testing will become the gold standard to diagnose inherited ocular disorders or syndromes in the future.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Abstract
The braking indices of pulsars may contain important information about the internal physics of neutron stars (NSs), such as neutron superfluidity and internal magnetic fields. As a ...subsequent paper of Cheng et al., we perform the same analysis as that done in the previous paper to other young pulsars with a steady braking index,
n
. Combining the timing data of these pulsars with the theory of magnetic field decay, and using their measured magnetic tilt angles, we can set constraints on the number of precession cycles,
ξ
, which represents the interactions between superfluid neutrons and other particles in the NS interior. For the pulsars considered in this paper, the results show that
ξ
is within the range of a few ×10
3
to a few ×10
6
. Interestingly, for the Crab and Vela pulsars, the constraints on
ξ
obtained with our method are generally consistent with that derived from modeling of the glitch rise behaviors of the two pulsars. Furthermore, we find that the internal magnetic fields of pulsar with
n
< 3 may be dominated by the toroidal components. Our results may not only help to understand the interactions between the superfluid neutrons and other particles in the interior of NSs but also be important for the study of continuous gravitational waves from pulsars.
Stargardt disease (STGD1) is a common recessive hereditary macular dystrophy in early adulthood or childhood, with an estimated prevalence of 1:8000 to 1:10,000. ABCA4 is the causative gene for ...STGD1. The current study aims at identifying the novel disease-related ABCA4 variants in Han Chinese families with STGD1 using next-generation sequencing (NGS).
In the present study, 12 unrelated Han Chinese families (19 males and 17 females) with STGD1 were tested by panel-based NGS. In order to capture the coding exons and the untranslated regions (UTRs) plus 30 bp of intronic flanking sequences of 792 genes, which were closely associated with usual ophthalmic genetic disease, we designed a customized panel, namely, Target_Eye_792_V2 chip. STGD1 patients were clinically diagnosed by experienced ophthalmologists. All the detected variants were filtered and analyzed through the public databases and in silico programs to assess potential pathogenicity.
Twenty-one ABCA4 mutant variants were detected in 12 unrelated Han Chinese families with STGD1, containing 14 missense, three splicing, two frameshift, one small deletion, and one nonsense variants. Base on the American College of Medical Genetics (ACMG) guidelines, 8 likely pathogenic and 13 pathogenic variants were determined. The functional consequences of these mutant variants were predicted through in silico programs. Of the 21 mutant variants in ABCA4, two novel coding variants c.3017G > A and c.5167 T > C and one novel null variant c.3051-1G > A were detected in three unrelated probands.
By panel-based NGS, 21 ABCA4 variants were confirmed in 12 unrelated Han Chinese families. Among them, 3 novel mutant variants were found, which further expanded the ABCA4 mutation spectrum in STGD1 patients.
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