Genetic profile of syndromic retinitis pigmentosa in Portugal.

PURPOSE: Retinitis pigmentosa (RP) comprises a genetically and clinically heterogeneous group of inherited retinal degenerations, where 20-30% of patients exhibit extra-ocular manifestations (syndromic RP). Understanding the genetic profile of RP has important implications for disease prognosis and genetic counseling. This study aimed to characterize the genetic profile of syndromic RP in Portugal. METHODS: Multicenter, retrospective cohort study. Six Portuguese healthcare providers identified patients with a clinical diagnosis of syndromic RP and available genetic testing results. All patients had been previously subjected to a detailed ophthalmologic examination and clinically oriented genetic testing. Genetic variants were classified according to the American College of Medical Genetics and Genomics; only likely pathogenic or pathogenic variants were considered relevant for disease etiology. RESULTS: One hundred and twenty-two patients (53.3% males) from 100 families were included. Usher syndrome was the most frequent diagnosis (62.0%), followed by Bardet-Biedl (19.0%) and Senior-Løken syndromes (7.0%). Deleterious variants were identified in 86/100 families for a diagnostic yield of 86.0% (87.1% for Usher and 94.7% for Bardet-Biedl). A total of 81 genetic variants were identified in 25 different genes, 22 of which are novel. USH2A and MYO7A were responsible for most type II and type I Usher syndrome cases, respectively. BBS1 variants were the cause of Bardet-Biedl syndrome in 52.6% of families. Best-corrected visual acuity (BCVA) records were available at baseline and last visit for 99 patients (198 eyes), with a median follow-up of 62.0 months. The mean BCVA was 56.5 ETDRS letters at baseline (Snellen equivalent ~ 20/80), declining to 44.9 ETDRS letters (Snellen equivalent ~ 20/125) at the last available follow-up (p < 0.001). CONCLUSION: This is the first multicenter study depicting the genetic profile of syndromic RP in Portugal, thus contributing toward a better understanding of this heterogeneous disease group. Usher and Bardet-Biedl syndromes were found to be the most common types of syndromic RP in this large Portuguese cohort. A high diagnostic yield was obtained, highlighting current genetic testing capabilities in providing a molecular diagnosis to most affected individuals. This has major implications in determining disease-related prognosis and providing targeted genetic counseling for syndromic RP patients in Portugal.

Usher syndrome IIIA: a review of the disorder and preclinical research advances in therapeutic approaches.

Usher syndrome (USH) is an autosomal recessive disorder characterized by sensorineural hearing loss, progressive pigmentary retinopathy, and vestibular dysfunction. The degree and onset of hearing loss vary among subtypes I, II, and III, while blindness often occurs in the second to fourth decades of life. Usher type III (USH3), characterized by postlingual progressive sensorineural hearing loss, varying levels of vestibular dysfunction, and varying degrees of visual impairment, typically manifests in the first to second decades of life. While USH3 is rare, it is highly prevalent in certain populations. RP61, USH3, and USH3A symbolize the same disorder, with the latter symbol used more frequently in recent literature. This review focuses on the clinical features, epidemiology, molecular genetics, treatment, and research advances for sensory deficits in USH3A.

Molecular genetics of inherited retinal degenerations in Icelandic patients.

The study objective was to delineate the genetics of inherited retinal degenerations (IRDs) in Iceland, a small nation of 364.000 and a genetic isolate. Benefits include delineating novel pathogenic genetic variants and defining genetically homogenous patients as potential investigative molecular therapy candidates. The study sample comprised patients with IRD in Iceland ascertained through national centralized genetic and ophthalmological services at Landspitali, a national social support institute, and the Icelandic patient association. Information on patients' disease, syndrome, and genetic testing was collected in a clinical registry. Variants were reevaluated according to ACMG/AMP guidelines. Overall, 140 IRD patients were identified (point prevalence of 1/2.600), of which 70 patients had a genetic evaluation where two-thirds had an identified genetic cause. Thirteen disease genes were found in patients with retinitis pigmentosa, with the RLBP1 gene most common (n = 4). The c.1073 + 5G > A variant in the PRPF31 gene was homozygous in two RP patients. All tested patients with X-linked retinoschisis (XLRS) had the same possibly unique RS1 pathogenic variant, c.441G > A (p.Trp147X). Pathologic variants and genes for IRDs in Iceland did not resemble those described in ancestral North-Western European nations. Four variants were reclassified as likely pathogenic. One novel pathogenic variant defined a genetically homogenous XLRS patient group.

Characteristics of Retinitis Pigmentosa Associated with ADGRV1 and Comparison with USH2A in Patients from a Multicentric Usher Syndrome Study Treatrush.

In contrast to USH2A, variants in ADGRV1 are a minor cause of Usher syndrome type 2, and the associated phenotype is less known. The purpose of the study was to characterize the retinal phenotype of 18 ADGRV1 patients (9 male, 9 female; median age 52 years) and compare it with that of 204 USH2A patients (111 male, 93 female; median age 43 years) in terms of nyctalopia onset, best corrected visual acuity (BCVA), fundus autofluorescence (FAF), and optical coherence tomography (OCT) features. There was no statistical difference in the median age at onset (30 and 18 years; Mann-Whitney U test, p = 0.13); the mean age when 50% of the patients reached legal blindness (≥1.0 log MAR) based on visual acuity (64 years for both groups; log-rank, p = 0.3); the risk of developing advanced retinal degeneration (patch or atrophy) with age (multiple logistic regression, p = 0.8); or the frequency of cystoid macular edema (31% vs. 26%, Fisher's exact test, p = 0.4). ADGRV1 and USH2A retinopathy were indistinguishable in all major functional and structural characteristics, suggesting that the loss of function of the corresponding proteins produces similar effects in the retina. The results are important for counseling ADGRV1 patients, who represent the minor patient subgroup.

Identification and computational analysis of USH1C, and SLC26A4 variants in Pakistani families with prelingual hearing loss.

Hearing loss (HL) is clinically and genetically heterogeneous disorder and is the most frequent occurring sensory deficit in humans. This study was conducted to decipher the genetic cause of HL occurring in two large consanguineous Pakistani families (GCNF-01, GCNF-03). Family history and pure tone audiometry of both families suggested prelingual HL, while the affected individuals of GCNF-01 also had low vision and balance problems, consistent with cardinal features of Usher syndrome type I (USH1). Exome sequencing followed by segregating analysis revealed a novel splice site variant (c.877-1G > A) of USH1C occurring with USH1 phenotype in family GCNF01. While the affected individual of family GCNF-03 were homozygous for the c.716 T > A, p.(Val239Asp) previously reported pathogenic variant of SLC26A4. Both variants have very low frequencies in control database. In silico mutagenesis and 3-dimensional simulation analyses revealed that both variants have deleterious impact on the proteins folding and secondary structures. Our study expands the mutation spectrum of the HL genes and emphasizes the utility of exome sequencing coupled with bioinformatics tools for clinical genetic diagnosis, prognosis, and family counseling.

Spectrum of DNA variants for non-syndromic deafness in a large cohort from multiple continents.

Hearing loss is the most common sensory deficit in humans with causative variants in over 140 genes. With few exceptions, however, the population-specific distribution for many of the identified variants/genes is unclear. Until recently, the extensive genetic and clinical heterogeneity of deafness precluded comprehensive genetic analysis. Here, using a custom capture panel (MiamiOtoGenes), we undertook a targeted sequencing of 180 genes in a multi-ethnic cohort of 342 GJB2 mutation-negative deaf probands from South Africa, Nigeria, Tunisia, Turkey, Iran, India, Guatemala, and the United States (South Florida). We detected causative DNA variants in 25 % of multiplex and 7 % of simplex families. The detection rate varied between 0 and 57 % based on ethnicity, with Guatemala and Iran at the lower and higher end of the spectrum, respectively. We detected causative variants within 27 genes without predominant recurring pathogenic variants. The most commonly implicated genes include MYO15A, SLC26A4, USH2A, MYO7A, MYO6, and TRIOBP. Overall, our study highlights the importance of family history and generation of databases for multiple ethnically discrete populations to improve our ability to detect and accurately interpret genetic variants for pathogenicity.

Frequency of Usher syndrome type 1 in deaf children by massively parallel DNA sequencing.

Usher syndrome type 1 (USH1) is the most severe of the three USH subtypes due to its profound hearing loss, absent vestibular response and retinitis pigmentosa appearing at a prepubescent age. Six causative genes have been identified for USH1, making early diagnosis and therapy possible through DNA testing. Targeted exon sequencing of selected genes using massively parallel DNA sequencing (MPS) technology enables clinicians to systematically tackle previously intractable monogenic disorders and improve molecular diagnosis. Using MPS along with direct sequence analysis, we screened 227 unrelated non-syndromic deaf children and detected recessive mutations in USH1 causative genes in five patients (2.2%): three patients harbored MYO7A mutations and one each carried CDH23 or PCDH15 mutations. As indicated by an earlier genotype-phenotype correlation study of the CDH23 and PCDH15 genes, we considered the latter two patients to have USH1. Based on clinical findings, it was also highly likely that one patient with MYO7A mutations possessed USH1 due to a late onset age of walking. This first report describing the frequency (1.3-2.2%) of USH1 among non-syndromic deaf children highlights the importance of comprehensive genetic testing for early disease diagnosis.

Therapy strategies for Usher syndrome Type 1C in the retina.

The Usher syndrome (USH) is the most common form of inherited deaf-blindness with a prevalence of ~ 1/6,000. Three clinical subtypes (USH1-USH3) are defined according to the severity of the hearing impairment, the presence or absence of vestibular dysfunction and the age of onset of retinitis pigmentosa (RP). USH1 is the most severe subtype with congenital severe to profound hearing loss and onset of RP before puberty. Currently only the amelioration of the hearing deficiency is implemented, but no treatment of the senso-neuronal degeneration in the eye exists.In our studies we are focusing on the evaluation of gene-based therapies to cure the retinal degeneration of USH1C patients: (i) gene augmentation using recombinant adeno-associated virus, (ii) genome editing by homologous recombination mediated by zinc-finger nucleases and, (iii) read-through therapy using novel designer aminoglycosides and PTC124. Latter compounds target in-frame nonsense mutations which account for ~ 20 % of all USH cases.All analyzed gene-based therapy strategies lead to the restoration of USH protein expression. These adjustments may be sufficient to reduce the progression of retinal degeneration, which would greatly improve the life quality of USH patients.

The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B.

The MYO7A gene is known to be responsible for both syndromic hearing loss (Usher syndrome type1B:USH1B) and non-syndromic hearing loss including autosomal dominant and autosomal recessive inheritance (DFNA11, DFNB2). However, the prevalence and detailed clinical features of MYO7A-associated hearing loss across a large population remain unclear. In this study, we conducted next-generation sequencing analysis for a large cohort of 10,042 Japanese hearing loss patients. As a result, 137 patients were identified with MYO7A-associated hearing loss so that the prevalence among Japanese hearing loss patients was 1.36%. We identified 70 disease-causing candidate variants in this study, with 36 of them being novel variants. All variants identified in autosomal dominant cases were missense or in-frame deletion variants. Among the autosomal recessive cases, all patients had at least one missense variant. On the other hand, in patients with Usher syndrome, almost half of the patients carried biallelic null variants (nonsense, splicing, and frameshift variants). Most of the autosomal dominant cases showed late-onset progressive hearing loss. On the other hand, cases with autosomal recessive inheritance or Usher syndrome showed congenital or early-onset hearing loss. The visual symptoms in the Usher syndrome cases developed between age 5-15, and the condition was diagnosed at about 6-15 years of age.

Usher Syndrome on the Island of Ireland: A Genotype-Phenotype Review.

Purpose: Usher syndrome (USH) is a genetically heterogeneous group of autosomal recessive (AR) syndromic inherited retinal degenerations (IRDs) representing 50% of deaf-blindness. All subtypes include retinitis pigmentosa, sensorineural hearing loss, and vestibular abnormalities. Thorough phenotyping may facilitate genetic diagnosis and intervention. Here we report the clinical/genetic features of an Irish USH cohort. Methods: USH patients were selected from the Irish IRD registry (Target 5000). Patients were examined clinically (deep-phenotyping) and genetically using a 254 IRD-associated gene target capture sequencing panel, USH2A exon, and whole genome sequencing. Results: The study identified 145 patients (24.1% USH1 [n = 35], 73.8% USH2 [n = 107], 1.4% USH3 [n = 2], and 0.7% USH4 [n = 1]). A genetic diagnosis was reached in 82.1%, the majority (80.7%) being MYO7A or USH2A genotypes. Mean visual acuity and visual field (VF) were 0.47 ± 0.58 LogMAR and 31.3° ± 32.8°, respectively, at a mean age of 43 years. Legal blindness criteria were met in 40.7%. Cataract was present in 77.4%. ADGRV1 genotypes had the most VF loss, whereas USH2A patients had greater myopia and CDH23 had the most astigmatism. Variants absent from gnomAD non-Finnish Europeans and ClinVar represented more than 20% of the variants identified and were detected in ADGRV1, ARSG, CDH23, MYO7A, and USH2A. Conclusions: USH is a genetically diverse group of AR IRDs that have a profound impact on affected individuals and their families. The prevalence and phenotype/genotype characteristics of USH in Ireland have, as yet, gone unreported. Understanding the genotype of Irish USH patients may guide clinical and genetic characterization facilitating access to existing/novel therapeutics.

Sensory and demographic characteristics of deafblindness rehabilitation clients in Montréal, Canada.

PURPOSE: Demographic changes are increasing the number of older adults with combined age-related vision and hearing loss, while medical advances increase the survival probability of children with congenital dual (or multiple) impairments due to pre-maturity or rare hereditary diseases. Rehabilitation services for these populations are highly in demand since traditional uni-sensory rehabilitation approaches using the other sense to compensate are not always utilizable. Very little is currently known about the client population characteristics with dual sensory impairment. The present study provides information about demographic and sensory variables of persons in the Montreal region that were receiving rehabilitation for dual impairment in December 2010. This information can inform researchers, clinicians, educators, as well as administrators about potential research and service delivery priorities. METHOD: A chart review of all client files across the three rehabilitation agencies that offer integrated dual sensory rehabilitation services in Montreal provided data on visual acuity, visual field, hearing detection thresholds, and demographic variables. RESULTS: The 209 males and 355 females ranged in age from 4months to 105years (M=71.9, S.D.=24.6), indicating a prevalence estimate for dual sensory impairment at 15/100000. Only 5.7% were under 18years of age, while 69.1% were over the age of 65years, with 43.1% over the age of 85years. The diagnostic combination that accounted for 31% of the entire sample was age-related macular degeneration with presbycusis. Their visual and auditory measures indicated that older adults were likely to fall into moderate to severe levels of impairment on both measures. Individuals with Usher Syndrome comprised 20.9% (n=118) of the sample. CONCLUSION: The age distribution in this sample of persons with dual sensory impairment indicates that service delivery planning will need to strongly consider the growing presence of older adults as the baby-boomers approach retirement age. The distribution of their visual and auditory limits indicates that the large majority of this client group has residual vision and hearing that can be maximized in the rehabilitation process in order to restore functional abilities and social participation. Future research in this area should identify the specific priorities in both rehabilitation and research in individuals affected with combined vision and hearing loss.

Retinitis pigmentosa in Usher syndrome in India: Electronic medical records driven big data analytics: Report III.

Purpose: To describe the clinical presentation and demographic distribution of retinitis pigmentosa (RP) in patients with Usher syndrome (USH). Methods: This is a cross-sectional observational hospital-based study including patients presenting between March 2012 and October 2020. In total, 401 patients with a clinical diagnosis of USH and RP in at least one eye were included as cases. The data were retrieved from the electronic medical record database. For better analysis, all 401 patients were reclassified into three subtypes (type 1, type 2, and type 3) based on the USH criteria. Results: In total, there were 401 patients with USH and RP, with a hospital-based prevalence rate of 0.02% or 2/10,000 population. Further, 353/401 patients were subclassified, with 121 patients in type 1, 146 patients in type 2, and 86 patients in the type 3 USH group. The median age at presentation was 27 years (IQR: 17.5-38) years. There were 246 (61.35%) males and 155 (38.65%) females. Males were more commonly affected in all three subtypes. Defective night vision was the predominant presenting feature in all types of USH (type 1: 43 (35.54%), type 2: 68 (46.58%), and type 3: 40 (46.51%) followed by defective peripheral vision. Patients with type 2 USH had more eyes with severe visual impairment. Conclusion: RP in USH is commonly bilateral and predominantly affects males in all subtypes. Patients with USH and RP will have more affection of peripheral vision than central vision. The key message of our study is early visual and hearing rehabilitation in USH patients with prompt referral to otolaryngologists from ophthalmologists and vice versa.

Molecular epidemiology of Usher syndrome in Italy.

PURPOSE: Usher syndrome is an autosomal recessive disorder characterized by hearing and vision loss. Usher syndrome is divided into three clinical subclasses (type 1, type 2, and type 3), which differ in terms of the severity and progression of hearing loss and the presence or absence of vestibular symptoms. Usher syndrome is defined by significant genetic heterogeneity, with at least 12 distinct loci described and 9 genes identified. This study aims to provide a molecular epidemiology report of Usher syndrome in Italy. METHODS: Molecular data have been obtained on 75 unrelated Italian patients using the most up-to date technology available for the screening of Usher syndrome gene mutations, i.e., the genotyping microarray developed by Asper Biotech (Tartu, Estonia), which simultaneously investigates 612 different marker positions using the well established arrayed primer extension methodology (APEX). RESULTS: Using this method, we found that 12% of cases (9 out of 75) harbored homozygous or compound heterozygous mutations in the gene positions analyzed, whereas 20% (15 out of 75) of the patients were characterized by the presence of only one mutated allele based on the positions analyzed. One patient was found to be compound heterozygous for mutations in two different genes and this represents an example of possible digenic inheritance in Usher syndrome. A total of 66.6% of cases (50 out of 75) were found to be completely negative for the presence of Usher syndrome gene mutations in the detected positions. Mutations detected by the array were confirmed by direct sequencing. CONCLUSIONS: These findings highlight the efficacy of the APEX-based genotyping approach in the molecular assessment of Usher patients, suggesting the presence of alleles not yet identified and/or the involvement of additional putative genes that may account for the pathogenesis of Usher syndrome.

A nationwide epidemiologic, clinical, genetic study of Usher syndrome in Japan.

BACKGROUND: Usher syndrome (USH) typically leads to deaf-blindness, requiring the provision of extensive education and rehabilitation services. Therefore, investigating the prevalence is crucial to requests for proper government support for USH patients. OBJECTIVE: The aim was to perform a nationwide epidemiologic survey of USH in Japan to estimate the prevalence of USH and reveal the relative frequency and characteristics of the three USH subtypes. METHODS: To estimate the number of USH patients visiting hospitals over a 1-year period, 1,628 hospitals were randomly selected from all Departments of Otorhinolaryngology and Ophthalmology in Japan. Subsequently, we collected data regarding the clinical characteristics of each patient treated and the results of genetic testing, if performed. RESULTS: We found that the prevalence of USH was at least 0.4 per 100,000 population. The frequency of clinical subtypes and causal genes for USH were consistent with previous reports. Also, we demonstrated the feasibility of genetic counseling for USH patients based on the results of genetic testing. CONCLUSION: USH is a rare disease, but requires social support due to the severity of symptoms. To minimize these issues, understanding the clinical characteristics and performing comprehensive genetic testing could allow early and accurate diagnosis as well as medical intervention.

Hearing Impairment with Monoallelic GJB2 Variants: A GJB2 Cause or Non-GJB2 Cause?

Recessive variants in GJB2 are the most common genetic cause of sensorineural hearing impairment. However, in many patients, only one variant in the GJB2 coding region is identified using conventional sequencing strategy (eg, Sanger sequencing), resulting in nonconfirmative diagnosis. Conceivably, there might be other unidentified pathogenic variants in the noncoding region of GJB2 or other deafness-causing genes in these patients. To address this, a next-generation sequencing-based diagnostic panel targeting the entire GJB2 gene and the coding regions of 158 other known deafness-causing genes was designed and applied to 95 patients with nonsyndromic sensorineural hearing impairment (including 81 Han Taiwanese and 14 Mongolian patients) in whom only a single GJB2 variant had been detected using conventional Sanger sequencing. The panel confirmed the genetic diagnosis in 24 patients (25.3%). Twenty-two of them had causative variants in several deafness-causing genes other than GJB2, including MYO15A, MYO7A, TECTA, POU4F3, KCNQ4, SLC26A4, OTOF, MT-RNR1, MITF, WFS1, and USH2A. The other two patients had causative variants in GJB2, including a Taiwanese patient with a mosaic maternal uniparental disomy c.235delC variant (approximately 69% mosaicism) and a Mongolian patient with compound heterozygous c.35dupG and c.35delG variants, which occurred at the same site. This study demonstrates the utility of next-generation sequencing in clarifying the genetic diagnosis of hearing-impaired patients with nonconfirmative GJB2 genotypes on conventional genetic examinations.

Spectrum of MYO7A Mutations in an Indigenous South African Population Further Elucidates the Nonsyndromic Autosomal Recessive Phenotype of DFNB2 to Include Both Homozygous and Compound Heterozygous Mutations.

MYO7A gene encodes unconventional myosin VIIA, which, when mutated, causes a phenotypic spectrum ranging from recessive hearing loss DFNB2 to deaf-blindness, Usher Type 1B (USH1B). MYO7A mutations are reported in nine DFNB2 families to date, none from sub-Saharan Africa.In DNA, from a cohort of 94 individuals representing 92 families from the Limpopo province of South Africa, eight MYO7A variations were detected among 10 individuals. Family studies identified homozygous and compound heterozygous mutations in 17 individuals out of 32 available family members. Four mutations were novel, p.Gly329Asp, p.Arg373His, p.Tyr1780Ser, and p.Pro2126Leufs*5. Two variations, p.Ser617Pro and p.Thr381Met, previously listed as of uncertain significance (ClinVar), were confirmed to be pathogenic. The identified mutations are predicted to interfere with the conformational properties of myosin VIIA through interruption or abrogation of multiple interactions between the mutant and neighbouring residues. Specifically, p.Pro2126Leufs*5, is predicted to abolish the critical site for the interactions between the tail and the motor domain essential for the autoregulation, leaving a non-functional, unregulated protein that causes hearing loss. We have identified MYO7A as a possible key deafness gene among indigenous sub-Saharan Africans. The spectrum of MYO7A mutations in this South African population points to DFNB2 as a specific entity that may occur in a homozygous or in a compound heterozygous state.

Prevalence and genetic-phenotypic characteristics of patients with USH2A mutations in a large cohort of Chinese patients with inherited retinal disease.

AIMS: To 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. METHODS: A total of 1381 patients with inherited retinal disease (IRD) were recruited. The phenotypic and genotypic information of patients with USH2A mutations was evaluated. RESULTS: The 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. CONCLUSIONS: This 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.

Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome.

Purpose: To describe the molecular epidemiology of nonsyndromic retinitis pigmentosa (RP) and Usher syndrome (US) in Italian patients. Methods: A total of 591 probands (315 with family history and 276 sporadics) were analyzed. For 155 of them, we performed a family segregation study, considering a total of 382 relatives. Probands were analyzed by a customized multigene panel approach. Sanger sequencing was used to validate all genetic variants and to perform family segregation studies. Copy number variants of selected genes were analyzed by multiplex ligation-dependent probe amplification. Four patients who tested negative to targeted next-generation sequencing analysis underwent clinical exome sequencing. Results: The mean diagnostic yield of molecular testing among patients with a family history of retinal disorders was 55.2% while the diagnostic yield including sporadic cases was 37.4%. We found 468 potentially pathogenic variants, 147 of which were unpublished, in 308 probands and 66 relatives. Mean ages of onset of the different classes of RP were autosomal dominant RP, 19.3 ± 12.6 years; autosomal recessive RP, 23.2 ± 16.6 years; X-linked RP, 13.9 ± 9.9 years; and Usher syndrome, 18.9 ± 9.5 years. We reported potential new genotype-phenotype correlations in three probands, two revealed by TruSight One testing. All three probands showed isolated RP caused by biallelic variants in genes usually associated with syndromes such as PERCHING and Senior-Loken or with retinal dystrophy, iris coloboma, and comedogenic acne syndrome. Conclusions: This is the largest molecular study of Italian patients with RP in the literature, thus reflecting the epidemiology of the disease in Italy with reasonable accuracy.

Correlation between Genotype and Phenotype in 69 Chinese Patients with USH2A Mutations: A comparative study of the patients with Usher Syndrome and Nonsyndromic Retinitis Pigmentosa.

PURPOSE: The aim of this study was to analyse 69 Chinese patients with USH2A mutations and to assess the genotype-phenotype correlation. METHODS: All 36 Usher syndrome type IIA patients and 33 nonsyndromic RP (retinitis pigmentosa) patients underwent clinical examinations. Eye examinations included best-corrected visual acuity, slit-lamp biomicroscopy, fundus examination with dilated pupils, fundus fluorescent angiography, visual field test, full-field electroretinography and optic coherence tomography; audiological assessment included pure tone audiometry and hearing thresholds. The molecular diagnosis of genotype combined the single-gene Sanger sequencing and next-generation sequencing. This study is a retrospective study. RESULTS: The mean age of first symptoms with Usher syndrome type IIa and nonsyndromic RP patients was 13.7 versus 29.8 years (ocular phenotypes, p < 0.001); 17.7 versus 29.9 years (nyctalopia, p < 0.001); 44.7 versus 54.8 years (low vision based on VF, p < 0.001); 41.7 versus 54.7 years (low vision based on VA, p < 0.001); and 46.0 versus 56.7 years (legal blindness based on VF, p < 0.001). There was significant difference in variants in the two groups (p < 0.05). Among patients with mutation c.2802T > G (p.Cys934Trp), more (66.7%) presented with normal hearing. All patients (3/3, 100%) with the variant c.8232G > C (p.Trp2744Cys) had hearing loss. Furthermore, we identified 23 novel variants in USH2A. CONCLUSIONS: Patients with Usher syndrome type IIa had an earlier onset of the disease, inferior visual function and presented with more truncating variants, compared with the nonsyndromic RP patients.

Frequency of Usher syndrome in two pediatric populations: Implications for genetic screening of deaf and hard of hearing children.

PURPOSE: Usher syndrome is a major cause of genetic deafness and blindness. The hearing loss is usually congenital and the retinitis pigmentosa is progressive and first noticed in early childhood to the middle teenage years. Its frequency may be underestimated. Newly developed molecular technologies can detect the underlying gene mutation of this disorder early in life providing estimation of its prevalence in at risk pediatric populations and laying a foundation for its incorporation as an adjunct to newborn hearing screening programs. METHODS: A total of 133 children from two deaf and hard of hearing pediatric populations were genotyped first for GJB2/6 and, if negative, then for Usher syndrome. Children were scored as positive if the test revealed > or =1 pathogenic mutations in any Usher gene. RESULTS: Fifteen children carried pathogenic mutations in one of the Usher genes; the number of deaf and hard of hearing children carrying Usher syndrome mutations was 15/133 (11.3%). The population prevalence was estimated to be 1/6000. CONCLUSION: Usher syndrome is more prevalent than has been reported before the genome project era. Early diagnosis of Usher syndrome has important positive implications for childhood safety, educational planning, genetic counseling, and treatment. The results demonstrate that DNA testing for Usher syndrome is feasible and may be a useful addition to newborn hearing screening programs.