Purpose: To characterize the genetic landscape of patients with suspected retinitis pigmentosa (RP) in the Chinese population.Design: Cohort study.Participants: A total of 1243 patients of Chinese origin with clinically suspected RP and their available family members (n ¼ 2701) were recruited.Methods: All patients and available family members were screened using multigene panel testing (including 586 eye disease-associated genes), followed by clinical variant interpretation.Main Outcome Measures: Diagnostic yield, the 17 most commonly implicated genes, age at onset, de novo mutations, and clinical usefulness of genetic testing.Results: Overall, 72.08% of patients received a molecular diagnosis, and the 17 top genes covered 75.63% of diagnostic cases. Diagnostic yield was higher among patients in the early-onset subgroup ( 5 years old, 79.58%) than in the childhood or adolescence-onset subgroup (6e16 years old, 73.74%) and late-onset subgroup (!17 years old, 65.99%). Moreover, different genes associated with different onset ages and subgroups with different onset ages showed a diverse mutation spectrum. Only 11 de novo mutations (3.18%) were identified. Furthermore, 16.84% of the patients who received a molecular diagnosis had refinement of the initial clinical diagnoses, and the remaining 83.16% received definite genetic subtypes of RP.Conclusions: This large cohort study provides population-based data of the genome landscape of patients with suspected RP in China. The diagnostic yield was significantly higher than that in previous studies, and the mutation spectrum is completely different with other populations. Genetic testing improves the chance to establish a precise diagnosis, identifies features not previously determined, and allows a more accurate refinement of risk to family members. Our results not only expand the existing genotypic spectrum but also serve as an efficient reference for the design of panel-based genetic diagnostic testing and genetic counseling for patients with suspected RP in

Purpose: To clarify the mutation spectrum and frequency of ABCA4 in a Chinese cohort with Stargardt disease (STGD1). Methods: A total of 153 subjects, comprising 25 families (25 probands and their family members) and 71 sporadic cases, were recruited for the analysis of ABCA4 variants. All probands with STGD1 underwent a comprehensive ophthalmologic examination. Overall, 792 genes involved in common inherited eye diseases were screened for variants by panel-based next-generation sequencing (NGS). Variants were filtered and analyzed to evaluate possible pathogenicity. Results: The total variant detection rate of at least one ABCA4 mutant allele was 84.3% (129/153): two or three disease-associated variants in 86 subjects (56.2%), one mutant allele in 43 subjects (28.1%), and no variants in 24 subjects (15.7%). Ninety-six variants were identified in the total cohort, which included 62 missense (64%), 15 splicing (16%), 11 frameshift (12%), 6 nonsense (6%), and 2 small insertion or deletion (2%) variants. Thirty-seven novel variants were found, including a de novo variant, c.4561delA. The most prevalent variant was c.101_106delCTTTAT (10.5%), followed by c.2894A > G (6.5%) and c.6563T > C (4.6%), in STGD1 patients from eastern China. Conclusion: Thirty-seven novel variants were detected using panel-based NGS, including one de novo variant, further extending the mutation spectrum of ABCA4. The common variants in a population from eastern China with STGD1 were also identified.

AimsTo investigate the frequency of USH2A mutation and the clinical and genetic differences between Usher syndrome type II (USH2) and retinitis pigmentosa (RP) in a large cohort of Chinese patients.MethodsA total of 1381 patients with inherited retinal disease (IRD) were recruited. The phenotypic and genotypic information of patients with USH2A mutations was evaluated.ResultsThe prevalence of patients with USH2A mutations was 15.75%, which was the most frequently detected gene in this cohort of patients. Hotspot of USH2A 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.ConclusionsThis study provides detailed clinical–genetic assessment of patients with USH2A mutations of Chinese origin, enabling precise genetic diagnoses, better management of these patients and putative therapeutic approaches.

BackgroundBestrophin-1 (BEST1) 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 BEST1 in a large cohort of Chinese patients with bestrophinopathy.MethodsPatients clinically suspected of bestrophinopathy were screened using multigene panel testing. All BEST1 variants were confirmed by Sanger sequencing, and validated in the families.FindingsA 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 BEST1 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%). BEST1 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 BEST1 in our cohort was 71.30%, no de novo mutations were identified.ConclusionThis is the largest study to date that provides major population-based data of the BEST1 mutation spectrum in China. Our results can serve as a well-founded reference for genetic counselling for patients with bestrophinopathy of Chinese origin.

BackgroundHeimler 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.ResultsTwo 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.ConclusionNext-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.