scholarly journals Variant Profiling of a Large Cohort of 138 Chinese Families With Autosomal Dominant Retinitis Pigmentosa

2021 ◽  
Vol 8 ◽  
Author(s):  
Ting Xiao ◽  
Yue Xie ◽  
Xin Zhang ◽  
Ke Xu ◽  
Xiaohui Zhang ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Retinal Dystrophy ◽  
Large Cohort ◽  
Chinese Patients ◽  
Screening Methods ◽  
Compound Heterozygous ◽  
Dominant Trait ◽  
Essential Information

Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy, and 15–25% of RP is transmitted as an autosomal dominant (ad) trait. The objectives of this study were to establish the variant profile in a large cohort of adRP families and to elucidate the variant spectrum of each adRP gene in Chinese patients. A total of 138 probands clinically diagnosed with RP as a presumed autosomal dominant trait were recruited. All probands underwent ophthalmic examinations by specialists. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger DNA sequencing, and multiplex ligation probe amplification assay, was used to detect variants. We identified heterozygous variants of 11 adRP genes in 73 probands, hemizygous, or heterozygous variants of X-linked RP genes in six patients, compound heterozygous variants of autosomal recessive RP genes in three pseudodominant families, and one heterozygous variant of one ad cone and rod dystrophy gene in one proband. One proband was found carrying both variants in RPGR and FAM161A. The overall detection rate was 59.4% (82/138). We detected 72 distinct disease-causing variants involving 16 RP genes and one cone-rod dystrophy gene; 33 of these variants have not been reported previously. Disease-causing variants were identified in the adRP genes in 52.9% of the families, followed by 4.3% in the X-linked RP genes, and 2.2% in the autosomal recessive genes. The most frequent mutant genes were RHO, PRPF31, RP1, SNRNP200, and PRPF8, which explained up to 78.0% of the genetically diagnosed families. Most of the variants identified in adRP genes were missense, and copy number variations were common (7/20) in the PRPF31 gene. We established the profile of the mutated genes and the variant spectrum of adRP genes in a large cohort of Chinese patients, providing essential information for genetic counseling and future development of therapeutics for retinal dystrophy inherited as a dominant trait.

scholarly journals New Compound Heterozygous CYP4V2 Mutations in Bietti Crystalline Corneoretinal Dystrophy

2020 ◽  
Author(s):  
Ting Wang ◽  
Qingshan Chen ◽  
Longhao Kuang ◽  
Jiantao Wang ◽  
Xiaohe Yan
Keyword(s):  
Autosomal Recessive ◽  
Frameshift Mutation ◽  
Retinal Dystrophy ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Retinal Diseases ◽  
Sequence Capture ◽  
Pathogenic Genes ◽  
Compound Heterozygous Mutations ◽  
Targeted Sequence Capture

Abstract Background: Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal dystrophy which is caused by the mutations of CYP4V2.Here we identified new CYP4V2compound heterozygous mutations in BCD.Methods:381 pathogenic genes related to retinal diseases were screened by targeted sequence capture array techniques and confirmed by Sanger sequencing.Results:Two female siblings with BCD carry two compound heterozygous mutations in CYP4V2. One was missense mutation c.1198C>T (p.R400C) and the other was frameshift mutation c.802-8_810delinsGC (p.V268_E329del).Optical coherence tomography (OCT) showed that the ellipsoid zone was absent in the macular regions and electroretinogram (ERG) revealed poor cone and rod responses. Conclusions:Newcompound heterozygous mutations in CYP4V2 are related to the BCD.Our study expands our knowledge of heterogenic phenotypes and genotypes through genetic diagnosis of the BCD patients.

THE ICHTHYOSIFORM DERMATOSES

PEDIATRICS ◽  
1968 ◽  
Vol 42 (6) ◽  
pp. 990-1004
Author(s):  
Nancy B. Esterly
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Clinical Investigation ◽  
Correct Diagnosis ◽  
Associated Anomalies ◽  
Dominant Trait ◽  
Autosomal Dominant Trait ◽  
Clinical Variants ◽  
Congenital Ichthyosiform Erythroderma ◽  
Mode Of Inheritance

The Term ichthyosis describes a group of heritable disorders which are characterized by cutaneous scaling. The visible scale differentiates these disorders from xeroderma in which the skin is dry but does not visibly desquamate. Many classifications of the ichthyoses have been proposed, but most are descriptive and contribute little to an understanding of etiology and pathogenesis. Often clinical variants or patients with minor associated anomalies have been categorized separately on an empirical basis and, in some cases, several names have been used for one entity to indicate severity of involvement. The most useful classification appears to be that of Wells and Kerr,1 who segregated the various types by their pattern of inheritance and retained the nomenclature in common usage. Differences in clinical features and histologic patterns also correlate with these genetically distinguishable types. Thus, with careful attention to the distribution and type of scale, family history, and skin histology, the physician will be able to classify patients in a meaningful way. Such an approach is helpful for several reasons. The prognosis, troublesome features, and degree of handicapping differ for the various ichthyoses. Sensible genetic counseling, an important part of the management of such patients, is possible only with the correct diagnosis. Moreover, clinical investigation of affected individuals will be further confused unless the entity under study is well defined. The need for an understanding of the physiologic and biochemical defects of ichthvotic skin is underscored by the limitations of currently available therapy. The four major types of ichthyosis include: (1) ichthyosis vulgaris, transmitted as an autosomal dominant trait; (2) sexlinked ichthyosis, transmitted as an Xlinked trait; (3) bullous congenital ichthyosiform erythroderma (CIE), inherited as an autosomal dominant trait; and (4) nonbulbus congenital ichthyosiform erythroderma, autosomal recessive mode of inheritance (Table I).

Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy

2019 ◽  
Vol 104 (7) ◽  
pp. 932-937 ◽  
Author(s):  
Ke Xu ◽  
Yue Xie ◽  
Tengyang Sun ◽  
Xiaohui Zhang ◽  
Chunjie Chen ◽  
...  
Keyword(s):  
Early Onset ◽  
Retinal Dystrophy ◽  
Case Series ◽  
Clinical Findings ◽  
Chinese Patients ◽  
Pcr Analysis ◽  
Common Mutation ◽  
Essential Information ◽  
Leber Congenital Amaurosis ◽  
Targeted Next Generation Sequencing

BackgroundLeber congenital amaurosis (LCA) and early onset severe retinal dystrophy (EOSRD) are clinically and genetically heterogeneous inherited retinal disorders that cause severe visual impairment in children. The objective of this study was to describe the mutation profile and phenotypic characteristics in Chinese patients with LCA or EOSRD.MethodsRetrospective consecutive case series (2010–2017) study was performed in 148 probands (91 with LCA and 57 with EOSRD). All patients underwent ophthalmic evaluation. Mutations were revealed using targeted next-generation sequencing, followed by Sanger DNA-sequencing and real-time quantitative PCR analysis.ResultsWe identified two diseasing-causing mutations in 88 unrelated patients, heterozygous autosomal dominant mutations in 11 probands and X-linked hemizygous mutations in 11 patients, for an overall mutation detection rate of 74.3% (110/148). We detected 158 different disease-causing mutations involving 14 LCA genes, 16 retinitis pigmentosa or cone-rod dystrophy genes and 3 syndromic retinal dystrophy genes. Of these 158 mutations, 98 were novel. The most common mutation was p.Q141X of AIPL1, with a gene-specific allele frequency of 60%. The first five most frequently mutated genes were AIPL1 (11.0%), RPGRIP1 (8.8%) and CEP290, GUCY2D and RPE65 (each 7.7%) in the patients with LCA and RPGR (12.3%), CRB1 (10.5%), RPE65 (10.5%), RDH12 (7.0%) and RP2 (5.3%) in the patients with EOSRD.ConclusionsOur results revealed that the mutation spectrum of patients with LCA differs from that of the patients with EOSRD and established the configuration of the mutation frequencies for each LCA gene in Chinese patients, thereby providing essential information for future genetic counselling and gene therapy.

scholarly journals Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Jin Kyun Oh ◽  
Jose Ronaldo Lima de Carvalho ◽  
Young Joo Sun ◽  
Sara Ragi ◽  
Jing Yang ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Dominant ◽  
Fundus Autofluorescence ◽  
Retinal Dystrophy ◽  
Protein Modeling ◽  
Fundus Photography ◽  
Imaging Biomarkers ◽  
Loss Of Function ◽  
Gene Panel Testing ◽  
Sd Oct

Abstract Background Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome. Results Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain. Conclusions We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.

scholarly journals Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

2020 ◽  
Vol 9 (7) ◽  
pp. 2224 ◽  
Author(s):  
Spencer M. Moore ◽  
Dorota Skowronska-Krawczyk ◽  
Daniel L. Chao
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Therapeutic Strategy ◽  
Leucine Zipper ◽  
Retinal Dystrophy ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor ◽  
Future Directions ◽  
Inherited Retinal Dystrophy ◽  
Visual Acuity Loss

Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) with a prevalence of 1:4000, characterized by initial rod photoreceptor loss and subsequent cone photoreceptor loss with accompanying nyctalopia, visual field deficits, and visual acuity loss. A diversity of causative mutations have been described with autosomal dominant, autosomal recessive, and X-linked inheritance and sporadic mutations. The diversity of mutations makes gene therapy challenging, highlighting the need for mutation-agnostic treatments. Neural leucine zipper (NRL) and NR2E3 are factors important for rod photoreceptor cell differentiation and homeostasis. Germline mutations in NRL or NR2E3 leads to a loss of rods and an increased number of cones with short wavelength opsin in both rodents and humans. Multiple groups have demonstrated that inhibition of NRL or NR2E3 activity in the mature retina could endow rods with certain properties of cones, which prevents cell death in multiple rodent RP models with diverse mutations. In this review, we summarize the literature on NRL and NR2E3, therapeutic strategies of NRL/NR2E3 modulation in preclinical RP models, as well as future directions of research. In summary, inhibition of the NRL/NR2E3 pathway represents an intriguing mutation agnostic and disease-modifying target for the treatment of RP.

Homozygous and Compound Heterozygous Mutations in the Telomerase Reverse Transcriptase Gene in Two Families with Spontaneous Dyskeratosis Congenita and Idiopathic Aplastic Anemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1675-1675
Author(s):  
Hong-Yan Du ◽  
Elena Pumbo ◽  
Peter Manley ◽  
David B. Wilson ◽  
Philip Mason ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Autosomal Recessive ◽  
Amino Acid Change ◽  
Autosomal Dominant ◽  
Bone Marrow Failure ◽  
Gene Mutations ◽  
Dyskeratosis Congenita ◽  
Compound Heterozygous ◽  
The Family ◽  
Tert Gene

Abstract Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome. Classically, DC presents with progressive bone marrow failure, abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia. The pattern of inheritance in families with DC suggests an X-linked recessive, an autosomal dominant, and an autosomal recessive form of DC. However, in the majority of patients the occurrence of the disease is sporadic or the family history is unknown. Mutations in four different genes have been associated with DC so far. Mutations in DKC1 have been shown to account for the X-linked form of DC and DKC1 de novo mutations account for about one third of male patients with sporadic disease. Mutations in the telomerase RNA TERC and in the catalytic subunit of telomerase, TERT, have been shown to be responsible for the autosomal dominant form of DC. Interestingly, patients with heterozygous mutations in TERC and TERT often show a milder form of disease and a later age of onset and often lack the classic mucocutaeous features, thus are classified as atypical DC. Very recently homozygosity for a mutation in NOP10 has been identified in one family with autosomal recessive disease. The products of the genes mutated in DC are all components of the telomerase complex, suggesting that disease in patients with DC is caused by a defect in telomere maintenance. Here we investigated two patients, one UPN # 199.001 presenting with the classic manifestations of DC and the other UPN# 284.001 presenting with progressive bone marrow failure but no other clinical features suggestive of DC. In both patients the telomeres measured in peripheral blood mononuclear cells were very short, being defined as being below the 1st percentile. Mutation analysis in the genes associated with DC revealed that patient 199.001 was homozygous for a novel TERT (C2110T) gene mutation, causing an amino acid change (P704S) within the RT domain of TERT. Both parents were heterozygous for the C to T transition. Interestingly however, the father was in addition heterozygote for a second mutation in TERT (C1234T; H412Y) a mutation which has previously been described and has been shown to reduce telomerase activity by 50%. Investigations of the family revealed that the parent’s were distantly related, explaining the same TERT sequence alteration in both parents. Both arms of the family contained members with pulmonary fibrosis. In the second patient 284.001 we identified two different novel TERT gene mutations. One A2537G causes the amino acid change Y846C in the RT domain of TERT whereas the other C2628G causes H876Q also in the RT domain. One of the mutations was inherited from each parent and the parent with the A2537G mutation also had very short telomeres. These two families illustrate that the pattern of inheritance in patients with DC may be complex and show for the first time that homozygous or compound heterozygous TERT gene mutation may be associated with DC. Co-dominance of the three different TERT gene mutations and the inheritance of short telomeres have possibly contributed to development of disease in these patients who were thought to have sporadic DC and idiopathic aplastic anemia.

scholarly journals Senior Loken syndrome with Atypical Retinitis Pigmentosa: a rare manifestation of rare disease

2018 ◽  
Vol 5 (2) ◽  
pp. 651
Author(s):  
Madhura S. ◽  
Sowrabha . ◽  
Manjunath . ◽  
Savitha M. R.
Keyword(s):  
Renal Transplantation ◽  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Retinal Dystrophy ◽  
Rare Condition ◽  
End Stage Kidney Disease ◽  
Rare Manifestation ◽  
Autosomal Recessive Condition ◽  
Urinary Concentrating Ability ◽  
End Stage

Senior Loken syndrome is an autosomal recessive condition characterized by combination of nephronophthisis and retinal degeneration. The earliest presenting features include polyuria and polydipsia secondary to impaired urinary concentrating ability. Nephronophthisis progresses to end stage kidney disease (ESKD) during second decade. The treatment of choice for ESKD due to nephronophthisis is renal transplantation. Retinal lesions are variable ranging from severe infantile onset retinal dystrophy to more typical retinitis pigmentosa. There is a spectrum of other features associated with this condition including skeletal, dermatological and cerebellar anomalies. Till date very few cases have been reported due to lack of awareness of this rare condition. Here, we report a case of Senior loken syndrome with atypical retinitis pigmentosa in a 14-year-old boy.

Management of retinitis pigmentosa

1980 ◽  
Vol 18 (11) ◽  
pp. 42-44
Keyword(s):  
Retinitis Pigmentosa ◽  
Night Blindness ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Visual Fields

The term retinitis pigmentosa (RP) describes a group of heritable disorders characterised by night blindness, constriction of the visual fields and specific changes in the fundi. It may be inherited as an autosomal dominant, an autosomal recessive or an X-linked trait, and each of these has a different prognosis and probably a different cause.

scholarly journals Prevalence of cystoid macular oedema, epiretinal membrane and cataract in retinitis pigmentosa

2018 ◽  
Vol 103 (8) ◽  
pp. 1163-1166 ◽  
Author(s):  
Gerald Liew ◽  
Stacey Strong ◽  
Patrick Bradley ◽  
Philip Severn ◽  
Anthony T Moore ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Macular Oedema ◽  
Epiretinal Membrane ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Cystoid Macular Oedema ◽  
Dominant Inheritance ◽  
Younger Age ◽  
Multivariable Analyses ◽  
Eye Clinic

Background/AimsTo report the prevalence of treatable complications (cystoid macular oedema, CME; epiretinal membrane, ERM and cataract) in patients with retinitis pigmentosa (RP).MethodsConsecutive patients with RP attending a tertiary eye clinic in 2012. Spectral domain-optical coherence tomography was used to determine presence of CME and ERM. Clinic records were reviewed to identify cataract and pseudophakia. Multivariable analyses adjusted for age, gender and other confounders.ResultsData are presented for 338 eyes from 169 patients. CME was present in 58.6% of patients and 50.9% of eyes and was bilateral in 73.7%. ERM, cataract and pseudophakia were present in 22.8%, 23.4% and 11.2% eyes, respectively. In multivariable analyses, CME was associated with younger age (OR 0.81, 95% CI 0.67 to 0.98) but not with gender. Patients with ERM and cataract/pseudophakia were less likely to also have CME (OR 0.19, 95% CI 0.09 to 0.40 and OR 0.37, 95% CI 0.16 to 0.84, respectively). CME was most prevalent in patients with autosomal-dominant inheritance (71.4%), followed by autosomal recessive/sporadic inheritance (58.9%) and least likely in persons with X linked inheritance (12.5%, p<0.001).ConclusionsThe prevalence of treatable RP complications is high and suggests it may be clinically beneficial to screen patients with RP to identify those who may benefit from current or future interventions.

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