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Aline Antonio - One of the best experts on this subject based on the ideXlab platform.
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A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family.
Molecular Vision, 2020Co-Authors: Isabelle Audo, Aline Antonio, Marieelise Lancelot, Saddek Mohand-said, Kinga Bujakowska, Aurore Germain, Christine Lonjou, Sophie Tronche, Wassila Carpentier, José-alain SahelAbstract:PURPOSE: To identify the genetic defect of a consanguineous Portuguese family with Rod-Cone Dystrophy and varying degrees of decreased audition. METHODS: A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive Rod-Cone Dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing. RESULTS: The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe Rod-Cone Dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment. CONCLUSIONS: We report a novel truncating mutation in DFNB31 associated with severe Rod-Cone Dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2.
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PHENOTYPIC CHARACTERISTICS OF Rod-Cone Dystrophy ASSOCIATED WITH MYO7A MUTATIONS IN A LARGE FRENCH COHORT.
Retina (Philadelphia Pa.), 2020Co-Authors: Samer Khateb, Christina Zeitz, Aline Antonio, Christel Condroyer, Crystel Bonnet, Saddek Mohand-said, Camille Andrieu, Marco Nassisi, Anne-françoise Roux, Céline DevismeAbstract:PURPOSE To document the Rod-Cone Dystrophy phenotype of patients with Usher syndrome type 1 (USH1) harboring MYO7A mutations. METHODS Retrospective cohort study of 53 patients (42 families) with biallelic MYO7A mutations who underwent comprehensive examination, including functional visual tests and multimodal retinal imaging. Genetic analysis was performed either using a multiplex amplicon panel or through direct sequencing. Data were analyzed with IBM SPSS Statistics software v. 21.0. RESULTS Fifty different genetic variations including 4 novel were identified. Most patients showed a typical Rod-Cone Dystrophy phenotype, with best-corrected visual acuity and central visual field deteriorating linearly with age. At age 29, binocular visual field demonstrated an average preservation of 50 central degrees, constricting by 50% within 5 years. Structural changes based on spectral domain optical coherence tomography, short wavelength autofluorescence, and near-infrared autofluorescence measurements did not however correlate with age. Our study revealed a higher percentage of epiretinal membranes and cystoid macular edema in patients with MYO7A mutations compared with Rod-Cone Dystrophy patients with other mutations. Subgroup analyses did not reveal substantial genotype-phenotype correlations. CONCLUSION To the best of our knowledge, this is the largest French cohort of patients with MYO7A mutations reported to date. Functional visual characteristics of this subset of patients followed a linear decline as in other typical Rod-Cone Dystrophy, but structural changes were variable indicating the need for a case-by-case evaluation for prognostic prediction and choice of potential therapies.
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Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations in PDE6A and PDE6B.
JAMA ophthalmology, 2019Co-Authors: Samer Khateb, Cecile Mejecase, Aline Antonio, Christel Condroyer, Vanessa Démontant, Saddek Mohand-said, Marine Foussard, Kinga Bujakowska, Marco Nassisi, José-alain SahelAbstract:Importance A precise phenotypic characterization of retinal dystrophies is needed for disease modeling as a basis for future therapeutic interventions. Objective To compare genotype, phenotype, and structural changes in patients with Rod-Cone Dystrophy (RCD) associated with mutations in PDE6A or PDE6B . Design, Setting, and Participants In a retrospective cohort study conducted in Paris, France, from January 2007 to September 2017, 54 patients from a cohort of 1095 index patients with RCD underwent clinical examination, including personal and familial history, best-corrected visual acuity (BCVA), color vision, slitlamp examination, full-field electroretinography, kinetic visual fields (VFs), retinophotography, optical coherence tomography, near-infrared fundus autofluorescence, and short-wavelength fundus autofluorescence imaging. Genotyping was performed using microarray analysis, targeted next-generation sequencing, and Sanger sequencing validation with familial segregation when possible. Data were analyzed from September 1, 2017, to February 1, 2018. Clinical variables were subsequently analyzed in 2018. Main Outcomes and Measures Phenotype and genotype comparison of patients carrying mutations in PDE6A or PDE6B . Results Of the 54 patients included in the study, 19 patients of 17 families (11 women [58%]; mean [SD] age at diagnosis, 14.83 [10.63] years) carried pathogenic mutations in PDE6A , and 35 patients of 26 families (17 women [49%]; mean [SD] age at diagnosis, 21.10 [11.56] years) had mutations in PDE6B , accounting for prevalences of 1.6% and 2.4%, respectively. Among 49 identified genetic variants, 14 in PDE6A and 15 in PDE6B were novel. Overall, phenotypic analysis revealed no substantial differences between the 2 groups except for night blindness as a presenting symptom that was noted to be more prevalent in the PDE6A than PDE6B group (80% vs 37%, respectively; P = .005). The mean binocular BCVA and VF decrease over time (measured as mean individual slopes coefficients) was comparable between patients with PDE6A and PDE6B mutations: 0.04 (0.12) vs 0.02 (0.05) for BCVA ( P = .89) and 14.33 (7.12) vs 13.27 (6.77) for VF ( P = .48). Conclusions and Relevance Mutations in PDE6A and PDE6B accounted for 1.6% and 2.4%, respectively, in a cohort of French patients with RCD. The functional and structural findings reported may constitute the basis of disease modeling that might be used for better prognostic estimation and candidate selection for photoreceptor therapeutic rescue.
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Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non-syndromic Rod-Cone Dystrophy.
Clinical genetics, 2018Co-Authors: Cecile Mejecase, Aline Antonio, Said El Shamieh, Christel Condroyer, Aurélie Hummel, Saddek Mohand-said, Camille Andrieu, Fiona Boyard, Marine Foussard, Steven B. BlanchardAbstract:Genetic investigations were performed in three brothers from a consanguineous union, the two oldest diagnosed with Rod-Cone Dystrophy (RCD), the youngest with early-onset cone-rod Dystrophy and the two youngest with nephrotic-range proteinuria. Targeted next-generation sequencing did not identify homozygous pathogenic variant in the oldest brother. Whole exome sequencing (WES) applied to the family identified compound heterozygous variants in CC2D2A (c.2774G>C p.(Arg925Pro); c.4730_4731delinsTGTATA p.(Ala1577Valfs*5)) in the three brothers with a homozygous deletion in CNGA3 (c.1235_1236del p.(Glu412Valfs*6)) in the youngest correcting his diagnosis to achromatopsia plus RCD. None of the three subjects had cerebral abnormalities or learning disabilities inconsistent with Meckel-Gruber and Joubert syndromes, usually associated with CC2D2A mutations. Interestingly, an African woman with RCD shared the CC2D2A missense variant (c.2774G>C p.(Arg925Pro); with c.3182+355_3825del p.(?)). The two youngest also carried compound heterozygous variants in CUBN (c.7906C>T rs137998687 p.(Arg2636*); c.10344C>G p.(Cys3448Trp)) that may explain their nephrotic-range proteinuria. Our study identifies for the first time CC2D2A mutations in isolated RCD and underlines the power of WES to decipher complex phenotypes.
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A Novel Nonsense Variant in REEP6 Is Involved in a Sporadic Rod-Cone Dystrophy Case
Clinical genetics, 2018Co-Authors: Cecile Mejecase, Aline Antonio, Said El Shamieh, Christel Condroyer, Melanie Letexier, Jean-paul Saraiva, José-alain Sahel, Saddek Mohand-said, Steven B. Blanchard, Isabelle AudoAbstract:Rod-Cone Dystrophy (RCD), also called retinitis pigmentosa, is the most common form of progressive inherited retinal disorders secondary to photoreceptor degeneration. It is a genetically heterogeneous disease characterized by night blindness, followed by visual field constriction and, in most severe cases, total blindness. The aim of our study was to identify the underlying gene defect leading to severe RCD in a 60-year-old woman. The patient's DNA was investigated by targeted next generation sequencing followed by whole exome sequencing. A novel nonsense variant, c.267G>A p.(Trp89*), was identified at a homozygous state in the proband in REEP6 gene, recently reported mutated in 7 unrelated families with RCD. Further functional studies will help to understand the physiopathology associated with REEP6 mutations that may be linked to a protein trafficking defect.
Saddek Mohand-said - One of the best experts on this subject based on the ideXlab platform.
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WDR34, a candidate gene for non‐syndromic rod‐cone Dystrophy
Clinical genetics, 2020Co-Authors: Maria Solaguren-beascoa, Cecile Mejecase, Marieelise Lancelot, Christel Condroyer, Saddek Mohand-said, Kinga Bujakowska, Lisa Emmenegger, Elise Orhan, Marion Neuillé, Christelle MichielsAbstract:Rod-Cone Dystrophy (RCD), also called retinitis pigmentosa, is characterized by rod followed by cone photoreceptor degeneration, leading to gradual visual loss. Mutations in over 65 genes have been associated with non-syndromic RCD explaining 60% to 70% of cases, with novel gene defects possibly accounting for the unsolved cases. Homozygosity mapping and whole-exome sequencing applied to a case of autosomal recessive non-syndromic RCD from a consanguineous union identified a homozygous variant in WDR34. Mutations in WDR34 have been previously associated with severe ciliopathy syndromes possibly associated with a retinal Dystrophy. This is the first report of a homozygous mutation in WDR34 associated with non-syndromic RCD.
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A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family.
Molecular Vision, 2020Co-Authors: Isabelle Audo, Aline Antonio, Marieelise Lancelot, Saddek Mohand-said, Kinga Bujakowska, Aurore Germain, Christine Lonjou, Sophie Tronche, Wassila Carpentier, José-alain SahelAbstract:PURPOSE: To identify the genetic defect of a consanguineous Portuguese family with Rod-Cone Dystrophy and varying degrees of decreased audition. METHODS: A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive Rod-Cone Dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing. RESULTS: The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe Rod-Cone Dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment. CONCLUSIONS: We report a novel truncating mutation in DFNB31 associated with severe Rod-Cone Dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2.
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PHENOTYPIC CHARACTERISTICS OF Rod-Cone Dystrophy ASSOCIATED WITH MYO7A MUTATIONS IN A LARGE FRENCH COHORT.
Retina (Philadelphia Pa.), 2020Co-Authors: Samer Khateb, Christina Zeitz, Aline Antonio, Christel Condroyer, Crystel Bonnet, Saddek Mohand-said, Camille Andrieu, Marco Nassisi, Anne-françoise Roux, Céline DevismeAbstract:PURPOSE To document the Rod-Cone Dystrophy phenotype of patients with Usher syndrome type 1 (USH1) harboring MYO7A mutations. METHODS Retrospective cohort study of 53 patients (42 families) with biallelic MYO7A mutations who underwent comprehensive examination, including functional visual tests and multimodal retinal imaging. Genetic analysis was performed either using a multiplex amplicon panel or through direct sequencing. Data were analyzed with IBM SPSS Statistics software v. 21.0. RESULTS Fifty different genetic variations including 4 novel were identified. Most patients showed a typical Rod-Cone Dystrophy phenotype, with best-corrected visual acuity and central visual field deteriorating linearly with age. At age 29, binocular visual field demonstrated an average preservation of 50 central degrees, constricting by 50% within 5 years. Structural changes based on spectral domain optical coherence tomography, short wavelength autofluorescence, and near-infrared autofluorescence measurements did not however correlate with age. Our study revealed a higher percentage of epiretinal membranes and cystoid macular edema in patients with MYO7A mutations compared with Rod-Cone Dystrophy patients with other mutations. Subgroup analyses did not reveal substantial genotype-phenotype correlations. CONCLUSION To the best of our knowledge, this is the largest French cohort of patients with MYO7A mutations reported to date. Functional visual characteristics of this subset of patients followed a linear decline as in other typical Rod-Cone Dystrophy, but structural changes were variable indicating the need for a case-by-case evaluation for prognostic prediction and choice of potential therapies.
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Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations in PDE6A and PDE6B.
JAMA ophthalmology, 2019Co-Authors: Samer Khateb, Cecile Mejecase, Aline Antonio, Christel Condroyer, Vanessa Démontant, Saddek Mohand-said, Marine Foussard, Kinga Bujakowska, Marco Nassisi, José-alain SahelAbstract:Importance A precise phenotypic characterization of retinal dystrophies is needed for disease modeling as a basis for future therapeutic interventions. Objective To compare genotype, phenotype, and structural changes in patients with Rod-Cone Dystrophy (RCD) associated with mutations in PDE6A or PDE6B . Design, Setting, and Participants In a retrospective cohort study conducted in Paris, France, from January 2007 to September 2017, 54 patients from a cohort of 1095 index patients with RCD underwent clinical examination, including personal and familial history, best-corrected visual acuity (BCVA), color vision, slitlamp examination, full-field electroretinography, kinetic visual fields (VFs), retinophotography, optical coherence tomography, near-infrared fundus autofluorescence, and short-wavelength fundus autofluorescence imaging. Genotyping was performed using microarray analysis, targeted next-generation sequencing, and Sanger sequencing validation with familial segregation when possible. Data were analyzed from September 1, 2017, to February 1, 2018. Clinical variables were subsequently analyzed in 2018. Main Outcomes and Measures Phenotype and genotype comparison of patients carrying mutations in PDE6A or PDE6B . Results Of the 54 patients included in the study, 19 patients of 17 families (11 women [58%]; mean [SD] age at diagnosis, 14.83 [10.63] years) carried pathogenic mutations in PDE6A , and 35 patients of 26 families (17 women [49%]; mean [SD] age at diagnosis, 21.10 [11.56] years) had mutations in PDE6B , accounting for prevalences of 1.6% and 2.4%, respectively. Among 49 identified genetic variants, 14 in PDE6A and 15 in PDE6B were novel. Overall, phenotypic analysis revealed no substantial differences between the 2 groups except for night blindness as a presenting symptom that was noted to be more prevalent in the PDE6A than PDE6B group (80% vs 37%, respectively; P = .005). The mean binocular BCVA and VF decrease over time (measured as mean individual slopes coefficients) was comparable between patients with PDE6A and PDE6B mutations: 0.04 (0.12) vs 0.02 (0.05) for BCVA ( P = .89) and 14.33 (7.12) vs 13.27 (6.77) for VF ( P = .48). Conclusions and Relevance Mutations in PDE6A and PDE6B accounted for 1.6% and 2.4%, respectively, in a cohort of French patients with RCD. The functional and structural findings reported may constitute the basis of disease modeling that might be used for better prognostic estimation and candidate selection for photoreceptor therapeutic rescue.
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Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non-syndromic Rod-Cone Dystrophy.
Clinical genetics, 2018Co-Authors: Cecile Mejecase, Aline Antonio, Said El Shamieh, Christel Condroyer, Aurélie Hummel, Saddek Mohand-said, Camille Andrieu, Fiona Boyard, Marine Foussard, Steven B. BlanchardAbstract:Genetic investigations were performed in three brothers from a consanguineous union, the two oldest diagnosed with Rod-Cone Dystrophy (RCD), the youngest with early-onset cone-rod Dystrophy and the two youngest with nephrotic-range proteinuria. Targeted next-generation sequencing did not identify homozygous pathogenic variant in the oldest brother. Whole exome sequencing (WES) applied to the family identified compound heterozygous variants in CC2D2A (c.2774G>C p.(Arg925Pro); c.4730_4731delinsTGTATA p.(Ala1577Valfs*5)) in the three brothers with a homozygous deletion in CNGA3 (c.1235_1236del p.(Glu412Valfs*6)) in the youngest correcting his diagnosis to achromatopsia plus RCD. None of the three subjects had cerebral abnormalities or learning disabilities inconsistent with Meckel-Gruber and Joubert syndromes, usually associated with CC2D2A mutations. Interestingly, an African woman with RCD shared the CC2D2A missense variant (c.2774G>C p.(Arg925Pro); with c.3182+355_3825del p.(?)). The two youngest also carried compound heterozygous variants in CUBN (c.7906C>T rs137998687 p.(Arg2636*); c.10344C>G p.(Cys3448Trp)) that may explain their nephrotic-range proteinuria. Our study identifies for the first time CC2D2A mutations in isolated RCD and underlines the power of WES to decipher complex phenotypes.
Isabelle Audo - One of the best experts on this subject based on the ideXlab platform.
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The genetics of Rod-Cone Dystrophy in Arab countries: a systematic review
European Journal of Human Genetics, 2020Co-Authors: Lama Jaffal, Christina Zeitz, Isabelle Audo, Hawraa Joumaa, Zamzam Mrad, Said El ShamiehAbstract:Since a substantial difference in the prevalence of genetic causes of Rod-Cone Dystrophy (RCD) was found among different populations, we conducted a systematic review of the genetic findings associated with RCD in Arab countries. Of the 816 articles retrieved from PubMed, 31 studies conducted on 407 participants from 11 countries were reviewed. Next-generation sequencing (NGS) was the most commonly used technique (68%). Autosomal recessive pattern was the most common pattern of inheritance (97%) and half of the known genes associated with RCD (32/63) were identified. In the Kingdom of Saudi Arabia, in addition to RP1 (20%) and TULP1 (20%), gene defects in EYS (8%) and CRB1 (7%) were also prevalently mutated. In North Africa, the main gene defects were in MERTK (18%) and RLBP1 (18%). Considering all countries, RP1 and TULP1 remained the most prevalently mutated. Variants in TULP1 , RP1, EYS, MERTK , and RLBP1 were the most prevalent, possibly because of founder effects. On the other hand, only ten Individuals were found to have dominant or X-linked RCD. This is the first time a catalog of RCD genetic variations has been established in subjects from the Arabi countries. Although the last decade has seen significant interest, expertise, and an increase in RCD scientific publication, much work needs to be conducted.
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A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family.
Molecular Vision, 2020Co-Authors: Isabelle Audo, Aline Antonio, Marieelise Lancelot, Saddek Mohand-said, Kinga Bujakowska, Aurore Germain, Christine Lonjou, Sophie Tronche, Wassila Carpentier, José-alain SahelAbstract:PURPOSE: To identify the genetic defect of a consanguineous Portuguese family with Rod-Cone Dystrophy and varying degrees of decreased audition. METHODS: A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive Rod-Cone Dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing. RESULTS: The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe Rod-Cone Dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment. CONCLUSIONS: We report a novel truncating mutation in DFNB31 associated with severe Rod-Cone Dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2.
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a novel heterozygous missense mutation in gnat1 leads to autosomal dominant riggs type of congenital stationary night blindness
BioMed Research International, 2018Co-Authors: Christina Zeitz, Cecile Mejecase, Mathilde Stevenard, Christelle Michiels, Isabelle Audo, Michael F. MarmorAbstract:Autosomal dominant congenital stationary night blindness (adCSNB) is rare and results from altered phototransduction giving a Riggs type of electroretinogram (ERG) with loss of the rod a-wave and small b-waves. These patients usually have normal vision in light. Only few mutations in genes coding for proteins of the phototransduction cascade lead to this condition; most of these gene defects cause progressive Rod-Cone Dystrophy. Mutation analysis of an adCSNB family with a Riggs-type ERG revealed a novel variant (c.155T>A p.Ile52Asn) in GNAT1 coding for the α-subunit of transducin, cosegregating with the phenotype. Domain predictions and 3D-modelling suggest that the variant does not affect the GTP-binding site as other GNAT1 adCSNB mutations do. It affects a predicted nuclear localization signal and a part of the first α-helix, which is distant from the GTP-binding site. The subcellular protein localization of this and other mutant GNAT1 proteins implicated in CSNB are unaltered in mammalian GNAT1 overexpressing cells. Our findings add a third GNAT1 mutation causing adCSNB and suggest that different pathogenic mechanisms may cause this condition.
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A Novel Nonsense Variant in REEP6 Is Involved in a Sporadic Rod-Cone Dystrophy Case
Clinical genetics, 2018Co-Authors: Cecile Mejecase, Aline Antonio, Said El Shamieh, Christel Condroyer, Melanie Letexier, Jean-paul Saraiva, José-alain Sahel, Saddek Mohand-said, Steven B. Blanchard, Isabelle AudoAbstract:Rod-Cone Dystrophy (RCD), also called retinitis pigmentosa, is the most common form of progressive inherited retinal disorders secondary to photoreceptor degeneration. It is a genetically heterogeneous disease characterized by night blindness, followed by visual field constriction and, in most severe cases, total blindness. The aim of our study was to identify the underlying gene defect leading to severe RCD in a 60-year-old woman. The patient's DNA was investigated by targeted next generation sequencing followed by whole exome sequencing. A novel nonsense variant, c.267G>A p.(Trp89*), was identified at a homozygous state in the proband in REEP6 gene, recently reported mutated in 7 unrelated families with RCD. Further functional studies will help to understand the physiopathology associated with REEP6 mutations that may be linked to a protein trafficking defect.
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ARL2BP mutations account for 0.1% of autosomal recessive Rod-Cone dystrophies with the report of a novel splice variant.
Clinical genetics, 2017Co-Authors: Isabelle Audo, Cecile Mejecase, Aline Antonio, Said El Shamieh, Christel Condroyer, Melanie Letexier, Christelle Michiels, Vanessa Démontant, Fiona Boyard, Jean-paul SaraivaAbstract:We report a novel ARL2BP splice site mutation after whole-exome sequencing (WES) applied to a Moroccan family including two sisters affected with autosomal recessive Rod-Cone Dystrophy (arRCD). Subsequent analysis of 844 index cases did not reveal further pathogenic chances in ARL2BP indicating that mutations in ARL2B are a rare cause of arRCD (about 0.1%) in a large cohort of French patients.
Christel Condroyer - One of the best experts on this subject based on the ideXlab platform.
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WDR34, a candidate gene for non‐syndromic rod‐cone Dystrophy
Clinical genetics, 2020Co-Authors: Maria Solaguren-beascoa, Cecile Mejecase, Marieelise Lancelot, Christel Condroyer, Saddek Mohand-said, Kinga Bujakowska, Lisa Emmenegger, Elise Orhan, Marion Neuillé, Christelle MichielsAbstract:Rod-Cone Dystrophy (RCD), also called retinitis pigmentosa, is characterized by rod followed by cone photoreceptor degeneration, leading to gradual visual loss. Mutations in over 65 genes have been associated with non-syndromic RCD explaining 60% to 70% of cases, with novel gene defects possibly accounting for the unsolved cases. Homozygosity mapping and whole-exome sequencing applied to a case of autosomal recessive non-syndromic RCD from a consanguineous union identified a homozygous variant in WDR34. Mutations in WDR34 have been previously associated with severe ciliopathy syndromes possibly associated with a retinal Dystrophy. This is the first report of a homozygous mutation in WDR34 associated with non-syndromic RCD.
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PHENOTYPIC CHARACTERISTICS OF Rod-Cone Dystrophy ASSOCIATED WITH MYO7A MUTATIONS IN A LARGE FRENCH COHORT.
Retina (Philadelphia Pa.), 2020Co-Authors: Samer Khateb, Christina Zeitz, Aline Antonio, Christel Condroyer, Crystel Bonnet, Saddek Mohand-said, Camille Andrieu, Marco Nassisi, Anne-françoise Roux, Céline DevismeAbstract:PURPOSE To document the Rod-Cone Dystrophy phenotype of patients with Usher syndrome type 1 (USH1) harboring MYO7A mutations. METHODS Retrospective cohort study of 53 patients (42 families) with biallelic MYO7A mutations who underwent comprehensive examination, including functional visual tests and multimodal retinal imaging. Genetic analysis was performed either using a multiplex amplicon panel or through direct sequencing. Data were analyzed with IBM SPSS Statistics software v. 21.0. RESULTS Fifty different genetic variations including 4 novel were identified. Most patients showed a typical Rod-Cone Dystrophy phenotype, with best-corrected visual acuity and central visual field deteriorating linearly with age. At age 29, binocular visual field demonstrated an average preservation of 50 central degrees, constricting by 50% within 5 years. Structural changes based on spectral domain optical coherence tomography, short wavelength autofluorescence, and near-infrared autofluorescence measurements did not however correlate with age. Our study revealed a higher percentage of epiretinal membranes and cystoid macular edema in patients with MYO7A mutations compared with Rod-Cone Dystrophy patients with other mutations. Subgroup analyses did not reveal substantial genotype-phenotype correlations. CONCLUSION To the best of our knowledge, this is the largest French cohort of patients with MYO7A mutations reported to date. Functional visual characteristics of this subset of patients followed a linear decline as in other typical Rod-Cone Dystrophy, but structural changes were variable indicating the need for a case-by-case evaluation for prognostic prediction and choice of potential therapies.
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Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations in PDE6A and PDE6B.
JAMA ophthalmology, 2019Co-Authors: Samer Khateb, Cecile Mejecase, Aline Antonio, Christel Condroyer, Vanessa Démontant, Saddek Mohand-said, Marine Foussard, Kinga Bujakowska, Marco Nassisi, José-alain SahelAbstract:Importance A precise phenotypic characterization of retinal dystrophies is needed for disease modeling as a basis for future therapeutic interventions. Objective To compare genotype, phenotype, and structural changes in patients with Rod-Cone Dystrophy (RCD) associated with mutations in PDE6A or PDE6B . Design, Setting, and Participants In a retrospective cohort study conducted in Paris, France, from January 2007 to September 2017, 54 patients from a cohort of 1095 index patients with RCD underwent clinical examination, including personal and familial history, best-corrected visual acuity (BCVA), color vision, slitlamp examination, full-field electroretinography, kinetic visual fields (VFs), retinophotography, optical coherence tomography, near-infrared fundus autofluorescence, and short-wavelength fundus autofluorescence imaging. Genotyping was performed using microarray analysis, targeted next-generation sequencing, and Sanger sequencing validation with familial segregation when possible. Data were analyzed from September 1, 2017, to February 1, 2018. Clinical variables were subsequently analyzed in 2018. Main Outcomes and Measures Phenotype and genotype comparison of patients carrying mutations in PDE6A or PDE6B . Results Of the 54 patients included in the study, 19 patients of 17 families (11 women [58%]; mean [SD] age at diagnosis, 14.83 [10.63] years) carried pathogenic mutations in PDE6A , and 35 patients of 26 families (17 women [49%]; mean [SD] age at diagnosis, 21.10 [11.56] years) had mutations in PDE6B , accounting for prevalences of 1.6% and 2.4%, respectively. Among 49 identified genetic variants, 14 in PDE6A and 15 in PDE6B were novel. Overall, phenotypic analysis revealed no substantial differences between the 2 groups except for night blindness as a presenting symptom that was noted to be more prevalent in the PDE6A than PDE6B group (80% vs 37%, respectively; P = .005). The mean binocular BCVA and VF decrease over time (measured as mean individual slopes coefficients) was comparable between patients with PDE6A and PDE6B mutations: 0.04 (0.12) vs 0.02 (0.05) for BCVA ( P = .89) and 14.33 (7.12) vs 13.27 (6.77) for VF ( P = .48). Conclusions and Relevance Mutations in PDE6A and PDE6B accounted for 1.6% and 2.4%, respectively, in a cohort of French patients with RCD. The functional and structural findings reported may constitute the basis of disease modeling that might be used for better prognostic estimation and candidate selection for photoreceptor therapeutic rescue.
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Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non-syndromic Rod-Cone Dystrophy.
Clinical genetics, 2018Co-Authors: Cecile Mejecase, Aline Antonio, Said El Shamieh, Christel Condroyer, Aurélie Hummel, Saddek Mohand-said, Camille Andrieu, Fiona Boyard, Marine Foussard, Steven B. BlanchardAbstract:Genetic investigations were performed in three brothers from a consanguineous union, the two oldest diagnosed with Rod-Cone Dystrophy (RCD), the youngest with early-onset cone-rod Dystrophy and the two youngest with nephrotic-range proteinuria. Targeted next-generation sequencing did not identify homozygous pathogenic variant in the oldest brother. Whole exome sequencing (WES) applied to the family identified compound heterozygous variants in CC2D2A (c.2774G>C p.(Arg925Pro); c.4730_4731delinsTGTATA p.(Ala1577Valfs*5)) in the three brothers with a homozygous deletion in CNGA3 (c.1235_1236del p.(Glu412Valfs*6)) in the youngest correcting his diagnosis to achromatopsia plus RCD. None of the three subjects had cerebral abnormalities or learning disabilities inconsistent with Meckel-Gruber and Joubert syndromes, usually associated with CC2D2A mutations. Interestingly, an African woman with RCD shared the CC2D2A missense variant (c.2774G>C p.(Arg925Pro); with c.3182+355_3825del p.(?)). The two youngest also carried compound heterozygous variants in CUBN (c.7906C>T rs137998687 p.(Arg2636*); c.10344C>G p.(Cys3448Trp)) that may explain their nephrotic-range proteinuria. Our study identifies for the first time CC2D2A mutations in isolated RCD and underlines the power of WES to decipher complex phenotypes.
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A Novel Nonsense Variant in REEP6 Is Involved in a Sporadic Rod-Cone Dystrophy Case
Clinical genetics, 2018Co-Authors: Cecile Mejecase, Aline Antonio, Said El Shamieh, Christel Condroyer, Melanie Letexier, Jean-paul Saraiva, José-alain Sahel, Saddek Mohand-said, Steven B. Blanchard, Isabelle AudoAbstract:Rod-Cone Dystrophy (RCD), also called retinitis pigmentosa, is the most common form of progressive inherited retinal disorders secondary to photoreceptor degeneration. It is a genetically heterogeneous disease characterized by night blindness, followed by visual field constriction and, in most severe cases, total blindness. The aim of our study was to identify the underlying gene defect leading to severe RCD in a 60-year-old woman. The patient's DNA was investigated by targeted next generation sequencing followed by whole exome sequencing. A novel nonsense variant, c.267G>A p.(Trp89*), was identified at a homozygous state in the proband in REEP6 gene, recently reported mutated in 7 unrelated families with RCD. Further functional studies will help to understand the physiopathology associated with REEP6 mutations that may be linked to a protein trafficking defect.
Marieelise Lancelot - One of the best experts on this subject based on the ideXlab platform.
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WDR34, a candidate gene for non‐syndromic rod‐cone Dystrophy
Clinical genetics, 2020Co-Authors: Maria Solaguren-beascoa, Cecile Mejecase, Marieelise Lancelot, Christel Condroyer, Saddek Mohand-said, Kinga Bujakowska, Lisa Emmenegger, Elise Orhan, Marion Neuillé, Christelle MichielsAbstract:Rod-Cone Dystrophy (RCD), also called retinitis pigmentosa, is characterized by rod followed by cone photoreceptor degeneration, leading to gradual visual loss. Mutations in over 65 genes have been associated with non-syndromic RCD explaining 60% to 70% of cases, with novel gene defects possibly accounting for the unsolved cases. Homozygosity mapping and whole-exome sequencing applied to a case of autosomal recessive non-syndromic RCD from a consanguineous union identified a homozygous variant in WDR34. Mutations in WDR34 have been previously associated with severe ciliopathy syndromes possibly associated with a retinal Dystrophy. This is the first report of a homozygous mutation in WDR34 associated with non-syndromic RCD.
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A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family.
Molecular Vision, 2020Co-Authors: Isabelle Audo, Aline Antonio, Marieelise Lancelot, Saddek Mohand-said, Kinga Bujakowska, Aurore Germain, Christine Lonjou, Sophie Tronche, Wassila Carpentier, José-alain SahelAbstract:PURPOSE: To identify the genetic defect of a consanguineous Portuguese family with Rod-Cone Dystrophy and varying degrees of decreased audition. METHODS: A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive Rod-Cone Dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing. RESULTS: The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe Rod-Cone Dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment. CONCLUSIONS: We report a novel truncating mutation in DFNB31 associated with severe Rod-Cone Dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2.
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targeted next generation sequencing identifies novel mutations in rp1 as a relatively common cause of autosomal recessive rod cone Dystrophy
BioMed Research International, 2015Co-Authors: Said El Shamieh, Aline Antonio, Elise Boulangerscemama, Marieelise Lancelot, Christel Condroyer, Melanie Letexier, Saddek Mohandsaid, Jean-paul Saraiva, Vanessa Démontant, José-alain SahelAbstract:We report ophthalmic and genetic findings in families with autosomal recessive Rod-Cone Dystrophy (arRCD) and RP1 mutations. Detailed ophthalmic examination was performed in 242 sporadic and arRCD subjects. Genomic DNA was investigated using our customized next generation sequencing panel targeting up to 123 genes implicated in inherited retinal disorders. Stringent filtering coupled with Sanger sequencing and followed by cosegregation analysis was performed to confirm biallelism and the implication of the most likely disease causing variants. Sequencing identified 9 RP1 mutations in 7 index cases. Eight of the mutations were novel, and all cosegregated with severe arRCD phenotype, found associated with additional macular changes. Among the identified mutations, 4 belong to a region, previously associated with arRCD, and 5 others in a region previously associated with adRCD. Our prevalence studies showed that RP1 mutations account for up to 2.5% of arRCD. These results point out for the necessity of sequencing RP1 when genetically investigating sporadic and arRCD. It further highlights the interest of unbiased sequencing technique, which allows investigating the implication of the same gene in different modes of inheritance. Finally, it reports that different regions of RP1 can also lead to arRCD.
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Whole-Exome Sequencing Identifies KIZ as a Ciliary Gene Associated with Autosomal-Recessive Rod-Cone Dystrophy
American journal of human genetics, 2014Co-Authors: Said El Shamieh, Aline Antonio, Christel Condroyer, Christelle Michiels, Vanessa Démontant, Fiona Boyard, Elise Orhan, Marion Neuillé, Angélique Terray, Marieelise LancelotAbstract:Rod-Cone Dystrophy (RCD), also known as retinitis pigmentosa, is a progressive inherited retinal disorder characterized by photoreceptor cell death and genetic heterogeneity. Mutations in many genes have been implicated in the pathophysiology of RCD, but several others remain to be identified. Herein, we applied whole-exome sequencing to a consanguineous family with one subject affected with RCD and identified a homozygous nonsense mutation, c.226C>T (p.Arg76∗), in KIZ, which encodes centrosomal protein kizuna. Subsequent Sanger sequencing of 340 unrelated individuals with sporadic and autosomal-recessive RCD identified two other subjects carrying pathogenic variants in KIZ: one with the same homozygous nonsense mutation (c.226C>T [p.Arg76∗]) and another with compound-heterozygous mutations c.119_122delAACT (p.Lys40Ilefs∗14) and c.52G>T (p.Glu18∗). Transcriptomic analysis in mice detected mRNA levels of the mouse ortholog (Plk1s1) in rod photoreceptors, as well as its decreased expression when photoreceptors degenerated in rd1 mice. The presence of the human KIZ transcript was confirmed by quantitative RT-PCR in the retina, the retinal pigment epithelium, fibroblasts, and whole-blood cells (highest expression was in the retina). RNA in situ hybridization demonstrated the presence of Plk1s1 mRNA in the outer nuclear layer of the mouse retina. Immunohistology revealed KIZ localization at the basal body of the cilia in human fibroblasts, thus shedding light on another ciliary protein implicated in autosomal-recessive RCD.
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CRB1 mutations in inherited retinal dystrophies.
Human Mutation, 2012Co-Authors: Kinga Bujakowska, Aline Antonio, Marieelise Lancelot, Melanie Letexier, Isabelle Audo, Jean-paul Saraiva, Saddek Mohand-said, Aurore Germain, Thierry Léveillard, Christine LonjouAbstract:Mutations in the CRB1 gene are associated with variable phenotypes of severe retinal dystrophies, ranging from leber congenital amaurosis (LCA) to Rod-Cone Dystrophy, also called retinitis pigmentosa (RP). Moreover, retinal dystrophies resulting from CRB1 mutations may be accompanied by specific fundus features: preservation of the para-arteriolar retinal pigment epithelium (PPRPE) and retinal telangiectasia with exudation (also referred to as Coats-like vasculopathy). In this publication, we report seven novel mutations and classify over 150 reported CRB1 sequence variants that were found in more that 240 patients. The data from previous reports were used to analyze a potential correlation between CRB1 variants and the clinical features of respective patients. This meta-analysis suggests that the differential phenotype of patients with CRB1 mutations is due to additional modifying factors rather than particular mutant allele combination.
