RP2 Gene Research Articles

Detecting Alu Element Insertion Variant in RP1 Gene Using Whole Genome Sequencing in Patients with Retinitis Pigmentosa.

Background/Objectives:Alu element insertion in the exon 4 of the RP1 gene was newly identified through whole genome sequencing (WGS). This was not detected in previous next-generation sequencing (NGS) analysis. We report three cases of Korean retinitis pigmentosa (RP) patients with compound heterozygous variants including Alu element insertion in the RP1 gene, indicating that Alu element insertion could be a cause of RP; Methods: Among patients diagnosed with RP having variants in the RP1 gene in the Asan Medical Center, WGS was additionally performed for genetically unsolved cases in previous NGS analysis to detect any presence of Alu element insertion. For cases detected to have Alu element insertion in the exon 4 of the RP1 gene, genetic and clinical characteristics were analyzed; Results: Among 16 patients with RP, 3 patients were detected to have Alu element insertion in the RP1 gene. Alu element insertion in the RP1 gene was also detected using WGS. It was revealed to be a pathogenic variant. Therefore, RP1 gene mutation was the confirmed genetic cause of RP for these three cases and genetic counseling was enabled for them; Conclusions: Alu element insertion in the RP1 gene could be a genetic cause of autosomal recessive RP patients with compound heterozygous variants. Through WGS, the identification of this pathogenic variant was possible. Confirmation is needed to check the presence of Alu element insertion in patients with compound heterozygous variants in the RP1 gene.

Late-Onset Slowly Progressing Cone/Macular Dystrophy in Patients With the Biallelic Hypomorphic Variant p.Arg1933Ter in RP1.

Homozygous hypomorphic variants of the RP1 gene, including c.5797C>T, p.Arg1933Ter, have traditionally been considered non-pathogenic. This study aimed to elucidate the clinical manifestations of late-onset, slowly progressive cone/macular dystrophy in patients homozygous for p.Arg1933Ter in the RP1 gene. Five patients with biallelic p.Arg1933Ter in RP1 were retrospectively recruited, and their clinical profiles were analyzed. Copy number variation analysis and Alu insertion assessment of genes associated with inherited retinal diseases were conducted. The results of comprehensive ophthalmological examinations, multimodal imaging, and full-field electroretinogram tests were analyzed. No specific sequencing errors or structural variations associated with the clinical phenotypes were identified. Alu element insertion in RP1 was not detected. The mean ± SD age at the first visit was 62.2 ± 9.8 years, with symptoms typically starting between 45 and 50 years of age. Two patients exhibited a mild form of cone/macular dystrophy, characterized by a relatively preserved fundus appearance and blurring of the ellipsoid zone on optical coherence tomography. Three patients had late-onset cone/macular dystrophy with significant atrophy. To our knowledge, this study is the first to report that a homozygous hypomorphic variant of RP1, previously considered non-pathogenic, leads to cone/macular dystrophy. The study introduces novel possibilities suggesting that the homozygous hypomorphic variant of RP1 may be linked to variant pathogenicity.

Characterisation of a LINE-1 Insertion in the RP1 Gene by Targeted Adaptive Nanopore Sequencing in a Family with Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of inherited degenerative retinal disorders affecting more than 1.5 million people worldwide. For 30-50% of individuals with RP, the genetic cause remains unresolved by current clinical diagnostic gene panels. It is likely explained by variants in novel RP-associated genes or noncoding regulatory regions, or by complex genetic alterations such as large structural variants. Recent developments in long-read sequencing techniques have opened an opportunity for efficient analysis of complex genetic variants. We analysed a Finnish family with dominantly inherited RP affecting six individuals in three generations. Two affected individuals underwent a comprehensive clinical examination in combination with a clinical diagnostic gene panel, followed by whole exome sequencing in our laboratory. They exhibited typical signs of RP, yet initial sequence analysis found no causative variants. Reanalysis of the sequencing data detected a LINE-1 (L1) retrotransposon insertion of unknown size in exon 4 of the RP1 axonemal microtubule-associated (RP1) gene. The large chimeric L1 insertion that segregated with the disease was further characterised using targeted adaptive nanopore sequencing of RP1, allowing us to identify a 5.6 kb L1 transposable element insertion in RP1 as the cause of RP in this family with dominantly inherited RP.

Genetic findings of individuals with inherited retinal diseases in Finland

Genetic research can benefit from population isolates like Finland, as they tend to have a high concentration of deleterious alleles on a small number of low‐frequency variants. To investigate gene findings from the patients with inherited retinal disorders (IRD) in Finland, retrospectively collected data from the patients with IRDs treated between January 1st of 2012, and December 31st of 2020 at the Department of Ophthalmology, Helsinki University Hospital. Of the 638 patients that underwent genetic testing, 79% received a likely genetic diagnosis (504/638). The genetic findings corresponded to autosomal recessive (AR) inheritance in 242 patients, X‐linked (XL) in 158, autosomal dominant (AD) in 94, and mitochondrial inheritance in 22 patients. The most common genetic diagnosis was X‐linked retinoschisis as 17% (84/504) harboured pathogenic variants in RS1. The most common retinitis pigmentosa genes with causative variants were CERKL (8.5%, 43/504), RPGR (5.8%, 24/504), and EYS (5%, 25/504). CERKL variant c.375C>G, p.(Cys125Trp) and EYS c.1155T>A, p.(Cys385Ter) are frequent founder mutations. The Stargardt disease is less common than in other Western countries, the pathogenic variants in the ABCA4 gene were found in 24 patients. Pathogenic variants were also found in CHM (26), and CLRN1 (16). The genetic landscape of IRDs in Finland differs from other Western countries due to its specific isolated population history. The high yield of genetic findings is possibly explained by the enriched founder mutations in the population. One‐fifth of the patients are lacking genetic diagnosis, which might be due to shortages in the testing methods, i.e., non‐coding variants and complex structural genomic variants are missing. To address this problem, we have been utilizing the whole genome and long‐read sequencing methods to uncover new pathogenic variants. In two families with IRDs, we have found large structural variants in the RP1 and PRPH2 genes using Nanopore long‐read sequencing. In the future, we try to utilize the advantages of the population isolate to find unknown genes causing IRDs.

RP2-Associated X-linked Retinopathy: Clinical Findings, Molecular Genetics, and Natural History in a Large Cohort of Female Carriers

RP2-associated retinopathy typically causes severe early onset retinitis pigmentosa (RP) in affected males. However, there is a scarcity of reports describing the clinical phenotype of female carriers. We tested the hypothesis that RP2 variants manifest in female carriers with a range of functional and anatomic characteristics. Retrospective case series. Females with disease-causing variants in RP2 were identified from investigation of pedigrees affected by RP2 retinopathy. All case notes and results of molecular genetic testing, retinal imaging (fundus autofluorescence imaging, optical coherence tomography (OCT)), and electrophysiology were reviewed. Forty pedigrees were investigated. Twenty-nine pedigrees had obligate carriers or molecularly confirmed female members with recorded relevant history and/or examination. For 8 pedigrees, data were available only from history, with patients reporting affected female relatives with RP in 4 cases and unaffected female relatives in the other 4 cases. Twenty-seven females from 21 pedigrees were examined by a retinal genetics specialist. Twenty-three patients (85%) reported no complaints and had normal vision and 4 patients had RP-associated complaints (15%). Eight patients had normal fundus examination (30%), 10 had a tapetal-like reflex (TLR; 37%), 5 had scattered peripheral pigmentation (19%), and the 4 symptomatic patients had fundus findings compatible with RP (15%). All asymptomatic patients with normal fundus, TLR, or asymptomatic pigmentary changes had a continuous ellipsoid zone on OCT when available. The electroretinograms revealed mild to severe photoreceptor dysfunction in 9 of 11 subjects, often asymmetrical, including 5 with pattern electroretinogram evidence of symmetrical (n = 4) or unilateral (n = 1 subject) macular dysfunction. Most carriers were asymptomatic, exhibiting subclinical characteristics such as TLR and pigmentary changes. However, female carriers of RP2 variants can manifest RP. Family history of affected females with RP does not exclude X-linked disease. The phenotypic spectrum as described herein has prognostic and counselling implications for RP2 carriers and patients.

Novel mutations of the X-linked genes associated with early-onset high myopia in five Chinese families

PurposeTo report novel pathogenic variants of X-linked genes in five Chinese families with early-onset high myopia (eoHM) by using whole-exome sequencing and analyzing the phenotypic features.Methods5 probands with X-linked recessive related eoHM were collected in Ningxia Eye Hospital from January 2021 to June 2022. The probands and their family members received comprehensive ophthalmic examinations,and DNA was abstracted from patients and family members. Whole-exome sequencing was performed on probands to screen the causative variants, and all suspected pathogenic variants were determined by Sanger sequencing and co-segregation analysis was performed on available family members. The pathogenicity of novel variants was predicted using silico analysis and evaluated according to ACMG guidelines. RT-qPCR was used to detect differences in the relative mRNAs expression of candidate gene in mRNAs available with the proband and family members in the pedigree 2. The relationship between genetic variants and clinical features was analyzed.ResultsAll probands were male, and all pedigrees conformed to an X-linked recessive inheritance pattern. They were diagnosed with high myopia at their first visits between 4 and 7 years old. Spherical equivalent ranged between − 6.00D and − 11.00D.The five novel hemizygous variants were found in the probands, containing frameshift deletion variant c.797_801del (p.Val266Alafs*75) of OPN1LW gene in the pedigree 1, nonsense variant c.513G > A (p.Trp171Ter)of RP2 gene in the pedigree 2, missense variant c.98G > T (p.Cys33Phe) of GPR143 gene in the pedigree 3, frameshift deletion variant c.1876_1877del (p.Met626Valfs*22) of FRMD7 gene in the pedigree 4 and inframe deletion variant c.670_ 675del (p.Glu192_ Glu193del) of HMGB3 gene in the pedigree 5. All variants were classified as pathogenic or likely pathogenic by the interpretation principles of HGMD sequence variants and ACMG guidelines. In family 2, RT-qPCR showed that the mRNA expression of RP2 gene was lower in the proband than in other normal family members, indicating that such variant caused an effect on gene function at the mRNA expression level. Further clinical examination showed that pedigrees 1, 2, 3, and 4 were diagnosed as X-linked recessive hereditary eye disease with early-onset high myopia, including quiescent cone dysfunction, retinitis pigmentosa, ocular albinism, and idiopathic congenital nystagmus respectively. The pedigree 5 had eoHM in the right eye and ptosis in both eyes.ConclusionIn this paper,we are the first to report five novel hemizygous variants in OPN1LW, RP2, GPR143, FRMD7, HMGB3 genes are associated with eoHM. Our study extends the genotypic spectrums for eoHM and better assists ophthalmologists in assessing, diagnosing, and conducting genetic screening for eoHM.

Clinical case of Wieacker–Wolff syndrome in a 5-year girl

Wieacker–Wolff syndrome (WWS) (OMIM 314580, 301041) is rare, slowly progressive, X-linked hereditary disorder. It is characterized by fetal akinesia, which results in congenital multiplex arthrogryposis, spasticity, and development delay. WWS is caused by the point mutations or extended deletions in the ZC4H2 gene, located on the long arm of the X chromosome (Xq11.2). Currently, about 100 cases have been described.
 We present the case of WWS 5-year girl. DNA diagnostic was performed using full exome sequencing and confirmed by Sanger sequencing. Determination of non-random X-chromosome inactivation was performed by methyl-sensitive PCR of GAAA-repeat RP2 gene. 
 The main clinical symptoms in our case are stiffness of large and small joints, specific facial phenotype, spasticity and lack of independent walking. We revealed heterozygous mutation с.22_23delAT (p.Met8fs) in ZC4H2 gene. Non-random inactivation of the X chromosome was detected (XCI = 96.1%).
 Conclusions. Clinical symptoms of the disease, the nature of the detected mutation and the literature data indicate to the presence of an X-linked dominant pattern of inheritance of WWS in our patient. We described the case referred to the group of ZC4H2-associated rare disorders.

Asymmetric presentation with a novel RP2 gene mutation in X-Linked retinitis pigmentosa: a case report

BackgroundWe present the detailed multimodal imaging analysis in a case of X-linked retinitis pigmentosa (XLRP) exhibiting a markedly asymmetric presentation with a novel RP2 mutation.Case presentationA 25-year-old woman complained of decreased vision in the right eye as well as night blindness. Her visual acuity was 20/100 (OD) and 20/20 (OS). Fundus examination revealed bone spicule pigmentation with tessellated changes in the fundus within the posterior pole. Optical coherence tomography (OCT) showed generalized disruption of foveal microstructures in the OD. No abnormal findings were identified, but localized ellipsoid zone band losses were observed on OCT in the OS. Fundus autofluorescence revealed multiple patchy hypo-autofluorescent lesions in the OD and a tapetal-like radial reflex against a dark background in the OS. Fluorescein angiography and OCT angiography revealed diffuse mottled hyperfluorescence with reduced retinal vessel density in the OD and no evidence of vascular compromise in the OS. Goldmann perimetry demonstrated a constricted visual field, and electrophysiological assessment revealed an extinguished rod response and a severely impaired cone response in the OD. Molecular genetic tests via next-generation sequencing revealed the pathogenic variant to be a heterozygous frameshift mutation in RP2 (RP2, p.Glu269Glyfs*7), resulting in premature termination of the protein.ConclusionsRandom X-inactivation may be attributed to interocular differences in the severity of XLRP in female carriers. A novel frameshift mutation in the RP2 gene and a comprehensive phenotypic evaluation in the current study may broaden the spectrum of the disease in XLRP carriers.

LINE‐1 insertion in the RP1 gene in a family with retinitis pigmentosa

AbstractPurpose: A family, with dominantly inherited retinal dystrophy in three generations, was negative for alterations in known causative genes upon initial analysis. We aimed to identify the causative pathogenic germline variant.Methods: Two of the six affected members were treated in the Helsinki University Hospital. The patients were subjected to clinical examination and retinal imaging, and the DNA samples to exome sequencing. The variants were called from the sequencing reads using Illumina DRAGEN™ Bio‐IT Platform. The identified pathogenic variant was visualized using Integrative Genomics Viewer (IGV) and confirmed by PCR and Oxford nanopore adaptive sequencing.Results: Two of the family members had typical retinitis pigmentosa with narrowed visual fields, peripheral retinal bone spicules, and cystic or atrophic changes in the macula. DRAGEN™ identified a LINE‐1 insertion in exon 4 of RP1 from the index that was also found in the cousin upon closer IGV inspection. The 5′‐end of the LINE‐1 insertion was confirmed by PCR using primers targeting the LINE‐1 fragment and RP1 exon 4 upstream of the suspected insertion site. However, PCR amplification over the LINE‐1 insertion was unsuccessful, indicating a considerably larger insertion than the 54‐bases called by DRAGEN™. Thus, Oxford nanopore adaptive sequencing will be used to resolve the true size and the breakpoints of the insertion.Conclusions: We report here that the retinitis pigmentosa of previously unresolved origin is caused by insertion of LINE‐1 transposon in the RP1 gene. Furthermore, NGS variant‐calling algorithms do not always detect aberrations from moving elements.

RP2-Associated X-linked Retinopathy: Clinical Findings, Molecular Genetics, and Natural History

To review and describe in detail the clinical course, functional and anatomic characteristics of RP2-associated retinal degeneration. Retrospective case series. Male participants with disease-causing variants in the RP2 gene. Review of all case notes and results of molecular genetic testing, retinal imaging (fundus autofluorescence [FAF] imaging, OCT), and electrophysiology assessment. Molecular genetic testing, clinical findings including best-corrected visual acuity (BCVA), qualitative and quantitative retinal imaging analysis, and electrophysiology parameters. Fifty-four molecularly confirmed patients were identified from 38 pedigrees. Twenty-eight disease-causing variants were identified, with 20 not previously clinically characterized. Fifty-three patients (98.1%) presented with retinitis pigmentosa. The mean age of onset (range ± standard deviation [SD]) was 9.6 years (1-57 ± 9.2 years). Forty-four patients (91.7%) had childhood-onset disease, with mean age of onset of 7.6 years. The most common first symptom was night blindness (68.8%). Mean BCVA (range ± SD) was 0.91 logarithm of the minimum angle of resolution (logMAR) (0-2.7 ± 0.80) and 0.94 logMAR (0-2.7 ± 0.78) for right and left eyes, respectively. On the basis of the World Health Organization visual impairment criteria, 18 patients (34%) had low vision. The majority (17/22) showed electroretinogram (ERG) evidence of a rod-cone dystrophy. Pattern ERG P50 was undetectable in all but 2 patients. A range of FAF findings was observed, from normal to advanced atrophy. There were no statistically significant differences between right and left eyes for ellipsoid zone width (EZW) and outer nuclear layer (ONL) thickness. The mean annual rate of EZW loss was 219 μm/year, and the mean annual decrease in ONL thickness was 4.93 μm/year. No patient with childhood-onset disease had an identifiable ellipsoid zone (EZ) after the age of 26 years at baseline or follow-up. Four patients had adulthood-onset disease and a less severe phenotype. This study details the clinical phenotype of RP2 retinopathy in a large cohort. The majority presented with early-onset severe retinal degeneration, with early macular involvement and complete loss of the foveal photoreceptor layer by the third decade of life. Full-field ERGs revealed rod-cone dystrophy in the vast majority, but with generalized (peripheral) cone system involvement of widely varying severity in the first 2 decades of life. Proprietary or commercial disclosure may be found after the references.

Identification of RP1 as the genetic cause of retinitis pigmentosa in a multi-generational pedigree using Extremely Low-Coverage Whole Genome Sequencing (XLC-WGS)

Motivation.Next-generation sequencing (NGS) technologies are decisive for discovering disease-causing variants, although their cost limits their utility in a clinical setting. A cost-mitigating alternative is an extremely low coverage whole-genome sequencing (XLC-WGS). We investigated its use to identify causal variants within a multi-generational pedigree of individuals with retinitis pigmentosa (RP). Causing progressive vision loss, RP is a group of genetically heterogeneous eye disorders with approximately 60 known causal genes. ResultsWe performed XLC-WGS in seventeen members of this pedigree, including three individuals with a confirmed diagnosis of RP. Sequencing data were processed using Illumina's DRAGEN pipeline and filtered using Illumina's genotype quality score metric (GQX). The resulting variants were analyzed using Expert Variant Interpreter (eVai) from enGenome as a prioritization tool. A nonsense known mutation (c.1625C > G; p.Ser542*) in exon 4 of the RP1 gene emerged as the most likely causal variant. We identified two homozygous carriers of this variant among the three sequenced RP cases and three heterozygous individuals with sufficient coverage of the RP1 locus. Our data show the utility of combining pedigree information with XLC-WGS as a cost-effective approach to identify disease-causing variants.

EP082: Associated recessive retinitis pigmentosa caused by paternal uniparental disomy

Variants in the RP1 gene have been associated with autosomal dominant and autosomal recessive inherited retinal dystrophies (adIRDs and arIRDs). We report on patient with juvenile-onset arIRD associated with RP1 variants inherited by uniparental disomy.

Congenital Adrenal Hyperplasia and Ehlers-Danlos Syndrome.

Congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency is an autosomal recessive disorder. The 21-hydroxylase enzyme P450c21 is encoded by the CYP21A2 gene located on chromosome 6p21.33 within the HLA major histocompatibility complex. This locus also contains the CYP21A1P, a non-functional pseudogene, that is highly homologous to the CYP21A2 gene. Other duplicated genes are C4A and C4B, that encode two isoforms of complement factor C4, the RP1 gene that encodes a serine/threonine protein kinase, and the TNXB gene that, encodes the extracellular matrix glycoprotein tenascin-X (TNX). TNX plays a role in collagen deposition by dermal fibroblasts and is expressed in the dermis of the skin and the connective tissue of the heart and skeletal muscle. During meiosis, misalignment may occur producing large gene deletions or gene conversion events resulting in chimeric genes. Chimeric recombination may occur between TNXB and TNXA. Three TNXA/TNXB chimeras have been described that differ in the junction site (CH1 to CH3) and result in a contiguous CYP21A2 and TNXB gene deletion, causing CAH-X syndrome. TNXB deficiency is associated with Ehlers Danlos syndrome (EDS). EDS comprises a clinically and genetically heterogeneous group of connective tissue disorders. As molecular analysis of the TNXB gene is challenging, the TNX-deficient type EDS is probably underdiagnosed. In this minireview, we will address the different strategies of molecular analysis of the TNXB-gene, as well as copy number variations and genetic status of TNXB in different cohorts. Furthermore, clinical features of EDS and clinical recommendations for long-term follow-up are discussed.

Cellular Cytotoxicity and Epigenetic Alteration in RP1 and RASSF1A Genes as Response for Anticancer Capabilities of Some Probiotic Bacteria in Breast Cancer

Cellular Cytotoxicity and Epigenetic Alteration in RP1 and RASSF1A Genes as Response for Anticancer Capabilities of Some Probiotic Bacteria in Breast Cancer

A Japanese boy with double diagnoses of 2p15p16.1 microdeletion syndrome and RP2-associated retinal disorder

2p15p16.1 microdeletion syndrome is a recently recognized congenital disorder characterized by developmental delay and dysmorphic features. RP2-associated retinal disorder (RP2-RD) is an X-linked inherited retinal disease with a childhood onset caused by a loss-of-function variant in the RP2 gene. Here, we describe a 14-year-old boy with double diagnoses of 2p15p16.1 microdeletion syndrome and RP2-RD. The recurrence risk of each condition and the indication for potential therapeutic options for RP2-RD are discussed.

Resistance in Maize (Zea mays) to Isolates of Puccinia sorghi from Eastern Australia

The causal agent of maize common rust (CR), Puccinia sorghi Schwein., has increased in incidence and severity in Australia in recent years, prompting the assessment of sources of resistance and a preliminary survey of the diversity of P. sorghi populations. The maize commercial hybrids tested carried no resistance to 14 isolates of P. sorghi and had infection types (IT) comparable to that of a susceptible check. The resistance gene Rp1_D that remained effective in the US for 35 years, was ineffective against seven of the 14 isolates. Maize lines carrying known Rp genes were inoculated with the five isolates considered most diverse based on year of collection (2018/2019), location (Queensland/Victoria), and host from which they were isolated (maize/sweet corn). Lines carrying the resistance genes RpG, Rp5, Rp1_E, Rp1_I, Rp1_L, RpGDJ, RpGJF and Rp5GCJ were resistant to all five isolates and to isolates collected in many agro-ecological regions. These lines were recommended as donors of effective resistance for maize breeding programs in Australia. Lines carrying no known resistance or resistance genes Rp8_A, Rp8_B, Rp1_J, Rp1_M, Rp7 and Rpp9 (conferring resistance to P. polysora Underw.) were susceptible to all five isolates. Differential lines carrying the resistance genes Rp1_B, Rp1_C, Rp1_D, Rp1_F, Rp1_K, Rp3_D, or Rp4_A were either resistant or susceptible depending upon the isolate used, showing that the isolates varied in virulence for these genes. Urediniospore production was reduced on adult compared to juvenile plants, presumably due to changes in plant physiology associated with age or the presence of adult plant resistance.

Whole-exome sequencing identified a novel mutation in CHM of a Chinese family

Choroideraemia (CHM) is a rare X-linked progressive-inherited retinal disease. In this study, we diagnosed and explored the genetic cause in a Chinese pedigree exhibiting nyctalopia and decreased visual acuity in early life. Clinical data and peripheral blood samples were collected from available family members. Sanger sequencing of RPGR and RP2 genes, and subsequently whole-exome sequencing was carried out to investigate the molecular cause. The proband was initially diagnosed as retinitis pigmentosa and experienced night blindness at an early age and decreased visual acuity in teens. The other affected males in this family suffered from the same problem. Direct sequencing failed to reveal the genetic cause and hence a novel hemizygous mutation c.861_862insGCTT was detected by WES in CHM gene resulting in a premature stop codon and a truncated protein. Subsequently, it was confirmed by Sanger sequencing and cosegregation analysis. We describe a novel mutation c.861_862insGCTT in CHM gene in a Chinese pedigree with choroideraemia. Our study emphasizes the utilization of next-generation sequencing in the diagnosis and genetic analysis of retinal diseases.

Clinical exome sequencing facilitates the understanding of genetic heterogeneity in Leber congenital amaurosis patients with variable phenotype in southern India

BackgroundLeber congenital amaurosis (LCA), primarily characterized by retinal degeneration is the most severe form of inherited retinal dystrophy (IRD) responsible for congenital blindness. The presence of phenotypic heterogeneity makes the diagnosis of LCA challenging, especially in the absence of pronounced disease pathognomonic, yet it can be well comprehended by employing molecular diagnosis. Therefore, the present study aimed to reveal the causative mutations in ten LCA patients with variable phenotypes using clinical exome sequencing (CES).MethodsCES was performed in ten unrelated LCA patients. Ophthalmic information and family history of all patients were obtained to make a meaningful interpretation. The clinical exome data was analyzed and prioritized using a bioinformatics pipeline to identify mutations, which was further validated by Sanger sequencing. Segregation analysis was also performed on available family members.ResultsCES led to the identification of causative mutations in nine LCA patients. Seven patients harbored a mutation in six LCA candidate genes, including RPE65, LCA5 (n = 2), CRX, PRPH2, CEP290, and ALMS1, while two patients possess a mutation in IFT80 and RP1, known to cause other diseases. Three novel mutations in LCA5 (c.1823del), CRX (c.848del) and CEP290 (c.2483G > T) were identified. The current study reports for the first time, a mutation in PRPH2, CEP290, and ALMS1 from the Indian population. Additionally, we observed a novel association of LCA phenotype with IFT80 known to cause Jeune syndrome. Based on the genetic finding, the patient AS09, who harbored a mutation in the RP1 gene, was re-diagnosed with early-onset retinitis pigmentosa.ConclusionIn conclusion, the results underline the importance of CES in clinically diagnosed LCA patients with variable phenotypes. The correlation between mutations in candidate genes and clinical phenotypes, helps to refine the clinical diagnosis. However, molecular evaluation with a larger cohort of LCA patients is needed for better understanding of the mutational spectrum in southern India.

Cellular Cytotoxicity and Epigenetic Alteration in RP1 and RASSF1A Genes as Response for Anticancer Capabilities of Some Probiotic Bacteria in Breast Cancer

Cellular Cytotoxicity and Epigenetic Alteration in RP1 and RASSF1A Genes as Response for Anticancer Capabilities of Some Probiotic Bacteria in Breast Cancer

Clinical characteristics and high resolution retinal imaging of retinitis pigmentosa caused by RP1 gene variants.

To report the clinical course and high resolution images of autosomal recessive retinitis pigmentosa (RP) associated with a variant of the RP1 gene (c.4052_4053ins328/p.Tyr1352Alafs*9; m1), a high frequency founder variant in Japanese RP patients. Retrospective case series. Nine patients from 5 unrelated Japanese families were studied. Five patients had the m1 variant homozygously, and 4 patients had the m1 variant compound heterozygously with another frameshift variant (c.4196delG/p.Cys1399Leufs*5). Ophthalmic examinations including adaptive optics (AO) fundus imaging were performed periodically. The fundus photographs, fundus autofluorescence (FAF) images, and optical coherence tomographic (OCT) images indicated severe retinal degeneration in all the patients involving the macula even at a young age (20s). The areas of surviving photoreceptors in the central macula were seen as hyper-autofluorescent regions in the FAF images and preserved outer retinal structure in the OCT images; they were identifiable in the AO fundus images in 8 eyes. The borders of the surviving photoreceptor areas were surrounded by hyporeflective clumps, presumably containing melanin, and the size of these areas decreased progressively during the 4-year follow-up period. The disappearance of the surviving photoreceptor areas was associated with complete blindness. Patients with RP associated with the m1 variant have a progressive and severe retinal degeneration that begins at an early age. Monitoring the surviving photoreceptor areas by AO fundus imaging can provide a more precise pathological record of retinal degeneration.