scholarly journals Identification of a PROM1 mutation in a Spanish family with inherited retinal dystrophies

2021 ◽  
Vol 15 (1) ◽  
pp. 314-317
Author(s):  
Pilar Llavero-Valero ◽  
María José Morillo-Sánchez ◽  
Nereida Bravo-Gil ◽  
Manuel Ramos Jiménez ◽  
Beatriz Ponte-Zuñiga ◽  
...  
Keyword(s):  
Family History ◽  
Autosomal Dominant ◽  
Phenotypic Variability ◽  
Clinical Manifestations ◽  
Macular Dystrophy ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Spanish Family ◽  
Mother And Daughter ◽  
Intrafamilial Phenotypic Variability

Background: We report a Spanish family, comprising an affected mother and daughter, respectively diagnosed with retinitis pigmentosa and Stargardt-like macular dystrophy, in whom we identified a PROM1 mutation. Methods: A custom gene panel consisting of 119 inherited retinal dystrophies (IRD)-genes was applied in the two affected individuals of this family and sequenced using the Illumina´s NextSeq500 platform. Results: The analysis of the resulting data allowed us to identify the pathogenic PROM1 mutation c.1117C>T (p.Arg373Cys) as the primary cause of the disease in both patients. No additional variants contributing to the extent of retinal dysfunction were detected. Conclusion: The variable expressivity of the detected PROM1 mutation is the most likely responsible for the intrafamilial phenotypic variability observed in this family. Screening of this mutation should be considered in patients with compatible clinical manifestations, especially when accompanied by an autosomal dominant family history.

scholarly journals Genome Editing as a Treatment for the Most Prevalent Causative Genes of Autosomal Dominant Retinitis Pigmentosa

2019 ◽  
Vol 20 (10) ◽  
pp. 2542 ◽  
Author(s):  
Michalitsa Diakatou ◽  
Gaël Manes ◽  
Beatrice Bocquet ◽  
Isabelle Meunier ◽  
Vasiliki Kalatzis
Keyword(s):  
Retinitis Pigmentosa ◽  
Genome Editing ◽  
Mutant Allele ◽  
Autosomal Dominant ◽  
Dominant Negative ◽  
Therapeutic Approaches ◽  
Autosomal Dominant Retinitis Pigmentosa ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Type Gene

Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of diseases with more than 250 causative genes. The most common form is retinitis pigmentosa. IRDs lead to vision impairment for which there is no universal cure. Encouragingly, a first gene supplementation therapy has been approved for an autosomal recessive IRD. However, for autosomal dominant IRDs, gene supplementation therapy is not always pertinent because haploinsufficiency is not the only cause. Disease-causing mechanisms are often gain-of-function or dominant-negative, which usually require alternative therapeutic approaches. In such cases, genome-editing technology has raised hopes for treatment. Genome editing could be used to (i) invalidate both alleles, followed by supplementation of the wild type gene, (ii) specifically invalidate the mutant allele, with or without gene supplementation, or (iii) to correct the mutant allele. We review here the most prevalent genes causing autosomal dominant retinitis pigmentosa and the most appropriate genome-editing strategy that could be used to target their different causative mutations.

scholarly journals Optical Coherence Tomography Angiography Imaging in Inherited Retinal Diseases

2019 ◽  
Vol 8 (12) ◽  
pp. 2078 ◽  
Author(s):  
Ong ◽  
Patel ◽  
Singh
Keyword(s):  
Optical Coherence Tomography ◽  
Optical Coherence Tomography Angiography ◽  
Imaging Modality ◽  
Retinal Disease ◽  
Macular Dystrophy ◽  
Retinal Diseases ◽  
Optical Coherence ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Powerful Research Tool

Optical coherence tomography angiography (OCTA) is a novel, noninvasive imaging modality that allows depth-resolved imaging of the microvasculature in the retina and the choroid. It is a powerful research tool to study the pathobiology of retinal diseases, including inherited retinal dystrophies. In this review, we provide an overview of the evolution of OCTA technology, compare the specifications of various OCTA devices, and summarize key findings from published OCTA studies in inherited retinal dystrophies including retinitis pigmentosa, Stargardt disease, Best vitelliform macular dystrophy, and choroideremia. OCTA imaging has provided new data on characteristics of these conditions and has contributed to a deeper understanding of inherited retinal disease.

Multicentric Carpotarsal Osteolysis Syndrome in a Mother and Daughter with a MAFB Missense Variant and Natural History of the Disease

2021 ◽  
pp. 1-6
Author(s):  
Kelin Chen ◽  
Malú Zamariolli ◽  
Maria de Fátima de Faria Soares ◽  
Vera Ayres Meloni ◽  
Maria Isabel Melaragno
Keyword(s):  
Natural History ◽  
Autosomal Dominant ◽  
Clinical Manifestations ◽  
Missense Variant ◽  
Heterozygous Variant ◽  
Tarsal Bones ◽  
Mother And Daughter ◽  
Dominant Disease ◽  
History Of

Multicentric carpotarsal osteolysis syndrome (MCTO; MIM #166300) is a rare skeletal disorder characterized by osteolysis affecting particularly the carpal, metacarpal, and tarsal bones, although other bones might be involved. MCTO is an autosomal dominant disease caused by heterozygous variants in the <i>MAFB</i> gene, frequently misdiagnosed as juvenile rheumatoid arthritis due to similar clinical manifestations. This study reports the first Brazilian family diagnosed with MCTO with progressive osteolysis of the carpal and tarsal bones, presenting a c.161C&#x3e;T (p.Ser54Leu) heterozygous variant in the <i>MAFB</i> gene, describing the clinical, radiological, and molecular findings, compared with literature data, and discussing the different clinical and molecular diagnosis, as well as the natural history of the disease. Since MCTO is a disorder with progressive symptoms, an early diagnosis is important to avoid unnecessary investigations and treatments and to provide the proper follow-up.

The Phenotypic Variability of Retinal Dystrophies Associated With Mutations in CRX, With Report of a Novel Macular Dystrophy Phenotype

2014 ◽  
Vol 55 (10) ◽  
pp. 6934-6944 ◽  
Author(s):  
S. Hull ◽  
G. Arno ◽  
V. Plagnol ◽  
S. Chamney ◽  
I. Russell-Eggitt ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Macular Dystrophy ◽  
Retinal Dystrophies

scholarly journals X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers

2012 ◽  
Vol 70 (7) ◽  
pp. 487-491 ◽  
Author(s):  
Charles Marques Lourenço ◽  
Gustavo Novelino Simão ◽  
Antonio Carlos Santos ◽  
Wilson Marques Jr
Keyword(s):  
Family History ◽  
Clinical Features ◽  
Wide Spectrum ◽  
Phenotypic Variability ◽  
Clinical Manifestations ◽  
Spastic Paraplegia ◽  
Heterozygous Female ◽  
Female Patients ◽  
History Of ◽  
Female Carriers

X-linked adrenoleukodystrophy (X-ALD) is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. OBJECTIVES: To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. METHODS: We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. RESULTS: The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. CONCLUSIONS: Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes.

scholarly journals Recurrence of the R947X Mutation in Unrelated Families with Autosomal Dominant Pseudohypoaldosteronism Type 1: Evidence for a Mutational Hot Spot in the Mineralocorticoid Receptor Gene

2006 ◽  
Vol 91 (9) ◽  
pp. 3671-3675 ◽  
Author(s):  
Fabio L. Fernandes-Rosa ◽  
Margaret de Castro ◽  
Ana Claudia Latronico ◽  
Wolfgang G. Sippell ◽  
Felix G. Riepe ◽  
...  
Keyword(s):  
Mineralocorticoid Receptor ◽  
Autosomal Dominant ◽  
Stop Codon ◽  
Hot Spot ◽  
Phenotypic Variability ◽  
Receptor Gene ◽  
Clinical Manifestations ◽  
Coding Region ◽  
Pseudohypoaldosteronism Type

Abstract Background: The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease characterized by congenital mineralocorticoid resistance of the kidney. Twenty-two different loss-of-function mutations in the mineralocorticoid receptor gene have been described in families with PHA1. These mutations were not recurrent and resulted in a large phenotypic variability. Objective: The objective of this study is to analyze the recurrence of an inactivating mutation in the mineralocorticoid receptor gene in unrelated families with autosomal dominant PHA1. Patients: Seventeen members from three unrelated families with autosomal dominant PHA1 were studied, including 11 affected patients with variable clinical manifestations. Fifty healthy subjects were used as controls. Methods: Genomic DNA was extracted, and the entire coding region of the mineralocorticoid receptor gene was submitted to automatic sequencing. Four dinucleotide microsatellite markers spanning a region of 3.2 cM in the human mineralocorticoid receptor gene locus, and two intragenic polymorphisms were used for haplotype analysis. Results: A heterozygous point mutation at codon 947 (c.2839C&gt;T) changing arginine to stop codon (R947X) was found in the three families. Different haplotypes segregated with the R947X mutation in each family, demonstrating the absence of a founder effect for this mutation. Conclusion: Codon 947 of the mineralocorticoid receptor is the first mutational hot spot for autosomal dominant PHA1.

scholarly journals Unravelling the Complexity of Inherited Retinal Dystrophies Molecular Testing: Added Value of Targeted Next-Generation Sequencing

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Isabella Bernardis ◽  
Laura Chiesi ◽  
Elena Tenedini ◽  
Lucia Artuso ◽  
Antonio Percesepe ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Genetic Alterations ◽  
Macular Dystrophy ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

To assess the clinical utility of targeted Next-Generation Sequencing (NGS) for the diagnosis of Inherited Retinal Dystrophies (IRDs), a total of 109 subjects were enrolled in the study, including 88 IRD affected probands and 21 healthy relatives. Clinical diagnoses included Retinitis Pigmentosa (RP), Leber Congenital Amaurosis (LCA), Stargardt Disease (STGD), Best Macular Dystrophy (BMD), Usher Syndrome (USH), and other IRDs with undefined clinical diagnosis. Participants underwent a complete ophthalmologic examination followed by genetic counseling. A custom AmpliSeq™ panel of 72 IRD-related genes was designed for the analysis and tested using Ion semiconductor Next-Generation Sequencing (NGS). Potential disease-causing mutations were identified in 59.1% of probands, comprising mutations in 16 genes. The highest diagnostic yields were achieved for BMD, LCA, USH, and STGD patients, whereas RP confirmed its high genetic heterogeneity. Causative mutations were identified in 17.6% of probands with undefined diagnosis. Revision of the initial diagnosis was performed for 9.6% of genetically diagnosed patients. This study demonstrates that NGS represents a comprehensive cost-effective approach for IRDs molecular diagnosis. The identification of the genetic alterations underlying the phenotype enabled the clinicians to achieve a more accurate diagnosis. The results emphasize the importance of molecular diagnosis coupled with clinic information to unravel the extensive phenotypic heterogeneity of these diseases.

MULTIPLE ENDOCRINE NEOPLASIA IN PRACTICE OF PRIMARY CARE AND FAMILY PHYISICIANS

2020 ◽  
pp. 11-15
Author(s):  
V. I Pozhar ◽  
O. V. Doroshenko ◽  
M. I. Shevchuk
Keyword(s):  
Family History ◽  
Genetic Analysis ◽  
Multiple Endocrine Neoplasia ◽  
Ganglion Cells ◽  
Family Members ◽  
Clinical Manifestations ◽  
Neurofibromatosis Type ◽  
Endocrine Tumors ◽  
Endocrine Neoplasia ◽  
Cutaneous Lichen Amyloidosis

Multiple endocrine neoplasia is characterized with a predisposition to tumors involving two or more endocrine glands. The four main forms of the disease are inherited as an autosomal dominant syndrome or may occur sporadically. In addition to these four forms, six other syndromes are associated with the presence of multiple endocrine and other neoplasms of the organs: hyperparathyroidism − jaw tumors, Carney complex, von Hippel−Lindau disease, neurofibromatosis type 1, Cowden syndrome and McCune − Albright syndrome. The diagnosis of multiple endocrine neoplasia syndrome can be established in humans by one of the three available criteria: clinical features, family history, genetic analysis. Mutation analysis during these syndromes is useful in clinical practice to confirm the clinical diagnosis; identifying family members who tolerate the mutation and need to be screened, and identifying family members who do not tolerate the mutation. Syndrome of multiple endocrine neoplasia (Wermer syndrome) is characterized by the presence of a triad of tumors, including tumors of the parathyroid glands, pheochromocytoma and tumors of the parathyroid gland. It occurs less frequently in combination with Hirschsprung's disease, caused by the absence of vegetative ganglion cells in the intestine terminal parts, that leads to colonic enlargement, severe constipation and obstruction. This syndrome may be associated with cutaneous lichen amyloidosis, the clinical manifestations of which are pruritus and lichenoid lesions, usually located in the upper back. A clinical case of MEN2 syndrome in a 52−year−old patient is presented. It is noted that for such patients, in addition to timely syndromic rather than component diagnosis of this endocrine multipathology, the spread of neoplastic process in medullary thyroid cancer to its capsule and surrounding tissues, as well as the presence of metastases in peripheral lymph nodes are important. As a rule, such patients cannot be timely cured. Key words: multiple endocrine neoplasia, endocrine tumors, genetic analysis, family history.

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