Novel Variants of RPGR in X-Linked Retinitis Pigmentosa Families and Genotype-Phenotype Correlation

2016 ◽  
Vol 27 (2) ◽  
pp. 240-248 ◽  
Author(s):  
Francesco Parmeggiani ◽  
Vanessa Barbaro ◽  
Angelo Migliorati ◽  
Paolo Raffa ◽  
Patrizia Nespeca ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Genetic Variants ◽  
Novel Mutation ◽  
Phenotypic Variability ◽  
Open Reading Frames ◽  
Pathological Effect ◽  
Exon 2 ◽  
Novel Variants ◽  
Ophthalmologic Examination ◽  
Exon 10

Purpose To identify novel mutations in the retinitis pigmentosa GTPase regulator ( RPGR) gene and retinitis pigmentosa 2 ( RP2) gene underlying X-linked retinitis pigmentosa (XLRP) and assess genotype-phenotype correlations. Methods The patient cohort, consisting of 13 individuals from 3 unrelated XLRP families, underwent comprehensive ophthalmologic examination. The open reading frames of RPGR and RP2 were analyzed with Sanger sequencing in each patient. The identified genetic variants were defined as mutations or polymorphisms on the basis of their pathological effect. Results We found 3 genetic variants: a novel mutation c.1591G>T in exon 14 and a novel polymorphism c.1105C>T in exon 10, resulting in p.Glu531* and p.Arg369Cys of RPGR gene, respectively, and one already known mutation c.413A>G in exon 2, resulting in a p.Glu138Gly of RP2 gene. Considering our XLRP probands, RPGR-related phenotypic damages were similar and less severe than those of the patient with the RP2 mutation. On the other hand, the female carriers of XLRP variants showed different RPGR-related consequences, ranging from rods hypofunctionality in c.1591G>T nonsense heterozygosity to no retinal changes in c.1105C>T polymorphic heterozygosity. Conclusions These findings broaden the spectrum of RPGR mutations and phenotypic variability of the disease, which will be useful for genetic consultation and diagnosis in the future.

OCT-angiography assessing quiescent and active choroidal neovascularization in retinitis pigmentosa associated with PRPH2 pathogenic variant

2021 ◽  
pp. 112067212110043
Author(s):  
Yousra Falfoul ◽  
Khaled EL Matri ◽  
Imen Habibi ◽  
Safa Halouani ◽  
Ahmed Chebil ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Choroidal Neovascularization ◽  
Multimodal Imaging ◽  
Phenotypic Variability ◽  
Pathogenic Variant ◽  
Exon 2 ◽  
Acute Visual Loss ◽  
Missense Variation ◽  
History Of

Purpose: To report multimodal imaging findings including optical coherence tomography angiography (OCT-A) of a patient presenting with a quiescent choroidal neovascularization (CNV) in one eye and an active CNV in the fellow eye, complicating retinitis pigmentosa (RP) linked to PRPH2 pathogenic variant, with follow-up and management of both eyes. Methods: Observational case report. Results: A 40-year-old female with history of autosomal dominant RP consulted for acute visual loss in her right eye (RE). Multimodal imaging including OCT-A confirmed the diagnosis of active type 2 CNV in the RE and highlighted an incidental asymptomatic non-exudative “quiescent” CNV in the left eye (LE). This complication was managed by intra-vitreal Bevacizumab injections in the RE and regular monitoring of the LE. Frequent follow-up could detect early CNV activation signs in LE allowing early treatment. Mutation analysis of PRPH2 exons identified a known heterozygous pathogenic missense variation c.646C>T, p.P216S in exon 2. Conclusion: Multimodal imaging and especially OCT-A can be of a great help in the diagnosis and the management of CNV complicating RP, even at the stage of quiescent CNV. In presence of neovascular complication, PRPH2 gene should be investigated because of its frequent macular involvement despite high phenotypic variability.

scholarly journals R761H M694I, M694V, V726A, R202Q, M680I AND E148Q MEFV GENE (FAMILIAL MEDITERRANEAN FEVER GENE) MUTATIONS IN THE AZERBAIJANİAN PATİENTS

2021 ◽  
Vol 06 (01) ◽  
pp. 50-51
Author(s):  
Huseynova Lala Huseynova Lala ◽  
Huseynova Qumru Huseynova Qumru
Keyword(s):  
Familial Mediterranean Fever ◽  
Mediterranean Region ◽  
Phenotypic Variability ◽  
Mefv Gene ◽  
Eastern Mediterranean Region ◽  
Nucleotide Sequences ◽  
Exon 2 ◽  
Mediterranean Fever ◽  
The Republic ◽  
Exon 10

MEFV gene (Familial Mediterranean Fever Gene) is located on chromosome 16 - 16.13.3., and it is composed of 3,242,028-3,256,776 nucleotides. It is specified as having an autosome-recessive hereditary type. Autosome-dominant hereditary species were also recorded(2,4). The MEFV RoRet genes family contains exon 10, consisting of 10,000 nucleotide sequences(5). The length of the transcript consists of 3.7 thousand nucleotide sequences consisting of 761 synthesized pyridine protein amino acid bases(1,3) MEFV gene researches were performed in the population of the Republic of Azerbaijan. Over 80 mutations have been identified so far. Four missense mutations (M680I, M694V, M694I, and V726A) in exon 10, together with E148Q in exon 2, account for the majority of FMF mutations in populations originating from areas around the eastern Mediterranean region. The various combinations of MEFV mutations are largely associated with the phenotypic variability of the disease. The most serious complication of FMF is the development of renal amyloidosis, which may be the only manifestation of the disease. The molecular-genetic study of the MEFV gene isolated from the genome DNA of 18 patients suspected of Family Disease Fever has identified 7 mutations: R761H M694I, M694V, V726A, R202Q, M680I and E148Q. All patients were of Azerbaijan origin, from the Mediterranean region of Azerbaijan. They were evaluated for clinical findings and family history of FMF. Seven mutations of MEFV gene were identified in heterozygous, homozygous and compound conditions: R761H M694I, M694V, V726A, R202Q, M680I and E148Q. The mutations E148Q and R202Q were discovered in exon 2 and R761H M694I, M694V, V726A, M680I were found in exon10 in the population of the Republic of Azerbaijan.

Greig Cephalopolysyndactyly Syndrome: Phenotypic Variability Associated with Variants in Two Different Domains of GLI3

2020 ◽  
Author(s):  
Hammal Khan ◽  
Sohail Ahmed ◽  
Sadia Nawaz ◽  
Wasim Ahmad ◽  
Muhammad Arshad Rafiq ◽  
...  
Keyword(s):  
Skeletal Development ◽  
Phenotypic Variability ◽  
Transcriptional Regulator ◽  
Molecular Study ◽  
Inherited Disorders ◽  
Pakistani Population ◽  
Greig Cephalopolysyndactyly Syndrome ◽  
Novel Variants ◽  
Limb Malformations ◽  
Pleiotropic Gene

Abstract Background GLI3 is a transcriptional regulator of several genes involved in mammalian skeletal development. Mutations in the pleiotropic gene GLI3 may result in different inherited disorders including Greig cephalopolysyndactyly syndrome (GCPS). GCPS is characterized by mild to severe craniofacial and limb malformations. Methods and Results Here, we report clinical and molecular study of 3 families with GCPS originated in different regions of Pakistan. Sanger sequencing revealed two novel variants including a frameshift [c. 3790_3791InsC, p.(Gly1236Argfs*11)] and a missense [c.1692A>G, p.(His536Arg)], and one previously reported variant [c.1965_1966delAT, p.(His627Glufs*48)] located in 2 different domains of the GLI3. Conclusion This study not only expanded spectrum of the mutations in the GLI3 but also highlighted phenotypic variability in the GCPS patients. This will facilitate diagnosis and genetic counseling of families with same and related disorders in the Pakistani population.

scholarly journals SAT0527 COMBINED EFFECT OF COMMON VARIANTS IN EXON 2 OR EXON 3 AND A PATHOGENIC MUTATION IN EXON 10 OF THE MEDITERRANEAN FEVER GENE ON INFLAMMASOME ACTIVATION IN JAPANESE PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1221.2-1221
Author(s):  
T. Koga ◽  
Y. Endo ◽  
K. Furukawa ◽  
K. Agematsu ◽  
A. Yachie ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Japanese Patients ◽  
Pathogenic Mutation ◽  
Inflammasome Activation ◽  
Combined Effects ◽  
Common Variants ◽  
Thoracic Pain ◽  
Exon 2 ◽  
Mediterranean Fever ◽  
Exon 10

Background:Familial Mediterranean fever (FMF) is an autoinflammatory disease that is caused by Mediterranean fever (MEFV) gene mutations. It is characterized by recurrent and self-limiting febrile attacks within a short period. Although the pathologic significance ofMEFVexon 2 or exon 3 common variants in patients with FMF is modest and these variants are usually associated with less severe clinical presentations of FMF (1, 2), their combined effects with pathogenic mutation in exon 10 remain to be evaluated.Objectives:To determine the combined effect of common variants on clinical manifestations and inflammasome activity, we compared the clinical and laboratory characteristics between the coexistence and non-coexistence ofMEFVexon 2 or exon 3 variants in patients with FMF that had a heterozygousMEFVexon 10 mutation.Methods:We excluded patients with FMF that had twoMEFVexon 10 mutations in one or more alleles and those withMEFVvariants in exons other than in exons 2, 3, or 10. Finally, we reviewed 131 Japanese patients with FMF that had a heterozygousMEFVexon 10 mutation, and they were divided into the groups with and withoutMEFVexon 2 or exon 3 variants of 34 and 97, respectively. All enrolled patients had only a heterozygous M694I mutation in exon 10 of theMEFVgene. We measured serum IL-18 levels at remission without febrile attacks in the groups with and withoutMEFVexon 2 or exon 3 variants of 9 and 31, respectively.Results:In the univariate analysis, the group with variants in exon 2 or exon 3 had significantly earlier onset (16.0 years v.s. 20.5 years, p = 0.04), a higher percentage of thoracic pain with febrile attacks (68% v.s. 44%, p = 0.02), a higher frequency of attack (1.0/month v.s. 0.5/month, p = 0.02), and a higher IL-18 level in the serum at remission (606.3 pg/ml v.s. 168.4 pg/ml, p = 0.04, Figure 1) compared to the group without these variants. Importantly, multivariate analyses showed that the coexistence ofMEFVexon 2 or exon 3 variants and an exon 10 mutation was independently and significantly associated with earlier onset of FMF (p = 0.049) and thoracic pain (p = 0.03).Figure 1.Conclusion:Our results suggest that the coexistence ofMEFVexon 2 or exon 3 variants and aMEFVexon 10 mutation has combined effects on inflammasome activation in the Japanese population.References:[1]Migita K, Uehara R, Nakamura Y, et al. Familial Mediterranean fever in Japan. Medicine (Baltimore). 2012 Nov;91(6):337-43.[2]Shinar Y, Livneh A, Langevitz P, Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol. 2000;27(7):1703.Disclosure of Interests:None declared

scholarly journals A novel mutation in the PRPH2 gene in a Chinese pedigree with retinitis pigmentosa and angle-closure glaucoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei-ning Li ◽  
Xiu-juan Du ◽  
Yu-ting Zhang ◽  
Le-yi Wang ◽  
Jing Zhu
Keyword(s):  
Visual Field ◽  
Retinitis Pigmentosa ◽  
Novel Mutation ◽  
Genetic Mutation ◽  
Angle Closure Glaucoma ◽  
Angle Closure ◽  
The Novel ◽  
Progressive Loss ◽  
Whole Exome ◽  
Transversion Mutation

Abstract Background Retinitis pigmentosa (RP) is a rare, progressive, and hereditary disorder that leads to the progressive loss of vision and visual field, and in some cases blindness. The specific relationship between RP and glaucoma has been debated for decades. Methods In this study, we examined a Han RP family with concomitant angle-closure glaucoma (ACG), performed an inductive analysis of their clinical features and assistant results, and applied whole-exome sequencing (WES) technology for a molecular diagnosis. Results A novel transversion mutation (c.626 T > A) was identified in the peripherin-2 (PRPH2) gene in the proband, resulting in the substitution of Valine to aspartic acid in codon 209. A full ophthalmic examination showed that the proband with the c.626 T > A mutation had a typical RP manifestation, with close angles; however, the proband’s elder brother, who lacked the novel mutation, had a normal fundus and open angles. Conclusion Our results extend the genetic mutation spectrum of PRPH2 in RP, and provide evidence to support a genetic correlation between RP and ACG.

scholarly journals Clinical follow-up of two Brazilian subjects with glucokinase-MODY (MODY2) with description of a novel mutation

2012 ◽  
Vol 56 (8) ◽  
pp. 490-495 ◽  
Author(s):  
Thais DellaManna ◽  
Magnus R. da Silva ◽  
Antonio Roberto Chacra ◽  
Ilda S. Kunii ◽  
Ana Luiza Rolim ◽  
...  
Keyword(s):  
Clinical Course ◽  
Novel Mutation ◽  
Microvascular Complications ◽  
Monogenic Diabetes ◽  
Pharmacological Interventions ◽  
Glucokinase Gene ◽  
Exon 2 ◽  
Slight Elevation

Mutations in the glucokinase gene (GCK) account for many cases of monogenic diabetes featuring maturity-onset diabetes of the young type 2 (MODY2). The clinical pattern of this form of hyperglycemia is rather stable, with a slight elevation in blood glucose, which is usually not progressive. Patients rarely require pharmacological interventions and microvascular complications related to diabetes are unusual. We describe the clinical follow-up of two cases of MODY2 with two different mutations in GCK gene, one in exon 7, p.Glu265Lys (c.793 G> A), which has been previously described, and a novel one, in exon 2, p.Ser69Stop (c. 206C> G). The clinical course of both cases shows similarity in metabolic control of this form of diabetes over the years. Arq Bras Endocrinol Metab. 2012;56(8):490-5

Novel combined insulin-like 3 variations of a single nucleotide in cryptorchidism

2019 ◽  
Vol 32 (9) ◽  
pp. 987-994 ◽  
Author(s):  
Xenophon Sinopidis ◽  
Roza Mourelatou ◽  
Eirini Kostopoulou ◽  
Alexia Karvela ◽  
Andrea-Paola Rojas-Gil ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Testicular Descent ◽  
Sequencing Analysis ◽  
Single Nucleotide ◽  
Allelic Variants ◽  
Exon 2 ◽  
Pcr Products ◽  
Exon 1 ◽  
Male Patients ◽  
Allelic Variations

Abstract Background Insulin-like 3 hormone (INSL3) is involved in the process of testicular descent, and has been thoroughly studied in cryptorchidism. However, INSL3 allelic variations found in the human genome were heterozygous and only a few of them were found exclusively in patients with cryptorchidism. Under this perspective, we aimed to study the presence of INSL3 allelic variations in a cohort of patients with cryptorchidism and to estimate their potential consequences. Methods Blood samples were collected from 46 male patients with non-syndromic cryptorchidism and from 43 age-matched controls. DNA extraction and polymerase chain reaction (PCR) were performed for exons 1 and 2 of the INSL3 gene in all subjects. Sequencing analysis was carried out on the PCR products. All data were grouped according to testicular location. Results Seven variations of a single nucleotide (SNVs) were identified both in patients with cryptorchidism and in controls: rs2286663 (c.27G > A), rs1047233 (c.126A > G) and rs6523 (c.178A > G) at exon 1, rs74531687 (c.191-30C > T) at the intron, rs121912556 (c.305G > A) at exon 2 and rs17750642 (c.*101C > A) and rs1003887 (c.*263G > A) at the untranslated region (UTR). The allelic variants rs74531687 and rs121912556 were found for the first time in the Greek population. The novel homozygotic combination of the three allelic variants rs1047233-rs6523-rs1003887 seemed to present a stronger correlation with more severe forms of cryptorchidism. Conclusions The combination of specific INSL3 SNVs rather than the existence of each one of them alone may offer a new insight into the involvement of allelic variants in phenotypic variability and severity.

scholarly journals A new MEFV gene mutation in an Iranian patient with familial Mediterranean fever

Reumatismo ◽  
2019 ◽  
Vol 71 (2) ◽  
pp. 85-87
Author(s):  
S. Farjadian ◽  
F. Bonatti ◽  
A. Soriano ◽  
M. Reina ◽  
A. Adorni ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Mutational Analysis ◽  
Novel Mutation ◽  
Present Report ◽  
Case Reports ◽  
Mefv Gene ◽  
Recurrent Fever ◽  
Iranian Patient ◽  
Mediterranean Fever ◽  
Exon 10

Familial mediterranean fever (FMF) is an inherited autoinflammatory disorder characterized by recurrent episodes of fever and painful inflammation involving the intra-abdominal organs, the lungs and the joints, which is highly prevalent in specific ethnic groups including the Iranians. We report a 12-year-old boy from Iran, with a clinical history of recurrent fever. Based on the suggestive clinical data, mutational analysis revealed the presence of the novel c.1945C>T heterozygous variant in exon 10, which leads to a leucine to phenylalanine change at position 649 of the protein. The mutation was inherited from the mother. This novel mutation lies in exon 10 of the MEFV gene, which encodes for a domain called B30.2-SPRY, located in the C-terminal region of the pyrin protein and contains the most frequent mutations associated with FMF. The present report expands the spectrum of MEFV gene mutations associated with FMF. The uniqueness of this study, compared with other published case reports, consists in the new mutation found in the MEFV gene. In fact, new mutations in this gene are of high interest, in order to better understand the role of this gene in autoinflammation.

Phenotypic high myopia in X-linked retinitis pigmentosa secondary to a novel mutation in the RPGR gene

2019 ◽  
Vol 40 (2) ◽  
pp. 170-176 ◽  
Author(s):  
Hortensia Sanchez Tocino ◽  
Cecilia Diez Montero ◽  
Ana Villanueva Gómez ◽  
Rosa Lobo Valentin ◽  
Javier Antonio Montero-Moreno
Keyword(s):  
Retinitis Pigmentosa ◽  
High Myopia ◽  
Novel Mutation

scholarly journals Mutation Spectrum and Genotype–Phenotype Analyses in a Pakistani Cohort With Hemophilia B

2017 ◽  
Vol 24 (5) ◽  
pp. 741-748 ◽  
Author(s):  
Muhammad Tariq Masood Khan ◽  
Arshi Naz ◽  
Jawad Ahmed ◽  
Tahir Shamsi ◽  
Shariq Ahmed ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Direct Sequencing ◽  
In Silico Analysis ◽  
Genetic Alterations ◽  
Factor Ix ◽  
Hemophilia B ◽  
Mutation Spectrum ◽  
Coagulation Activity ◽  
Exon 2 ◽  
Novel Variants

This study aimed to (1) identify F9 genetic alterations in patients with hemophilia B (HB) of Pakistani origin and (2) determine the genotype–phenotype relationships in these patients. Diagnosed cases of HB were identified through registries at designated tertiary health-care centers across the country. Consenting patients were enrolled into the study. The factor IX (FIX) coagulation activity (FIX:C) and key clinical features were recorded. Direct sequencing of F9 was carried out in all patients. All the variants identified were analyzed for functional consequences employing in silico analysis tools. Accession numbers from National Center of Biotechnology Information ClinVar database were retrieved for the novel variants. Genotype–FIX:C relationships were determined followed by FIX:C clinical phenotype assessment. A total of 52 patients with HB from 36 unrelated families were identified, which mainly comprised patients with moderate HB (n = 35; 67.3%). Among these, 35 patients from 22 unrelated families could be contacted and enrolled into the study. Missense variants were the most frequent (58.8%), followed by nonsense variants (17.6%). A missense, a short insertion, and a nonsense novel variants in exon 2, 6, and 7, respectively, were also identified. The disease manifested FIX:C heterogeneity in relation to the corresponding mutation in a significant number of cases. Clinical phenotype heterogeneity was also observed in relation to FIX:C-based severity assessment. We concluded that the registered FIX-deficient population of Pakistan mainly comprises moderate HB. F9 mutation spectrum in Pakistani patients with HB is heterogeneous. The HB population of Pakistan manifests a significant amount of genotype–FIX:C and FIX:C–clinical phenotype heterogeneities.

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