scholarly journals Recurrent AIPL1 c.487C>T truncating variant in Leber Congenital Amaurosis: Support of pathogenicity and regional implications

2018 ◽  
Author(s):  
Mohammed O.E. Abdallah ◽  
Mahmoud E. Koko ◽  
Shima Faisal ◽  
Melanie J. Newport ◽  
Muntaser E. Ibrahim
Keyword(s):  
Gene Therapy ◽  
Middle Eastern ◽  
Retinal Dystrophy ◽  
Genetic Diagnosis ◽  
Homozygous State ◽  
Leber Congenital Amaurosis ◽  
Healthy Mother ◽  
Whole Exome ◽  
The Family ◽  
Inherited Retinal Dystrophy

AbstractBackgroundLeber Congenital Amaurosis (LCA) is a clinically and genetically heterogeneous inherited retinal dystrophy characterized by early onset visual impairment caused by mutations in not less than 17 genes. AIPL1 mutations cause LCA type 4, comprising approximately 7% of LCA worldwide. The importance of establishing a genetic diagnosis lies in the promise of gene therapy demonstrated in mouse models.Resultswe genetically investigated a consanguineous Sudanese family with Leber Congenital Amaurosis. Eight members of the family were affected. Using whole exome sequencing in two siblings and their healthy mother, both inheritance-based and phenotype-based prioritization strategies converged to identify a truncating variant (rs62637009) in AIPL1, consistent with a diagnosis of LCA type 4. AIPL1 c.487C>T is an ultra-rare cause of LCA4 that was seen previously in homozygous state in a single Palestinian family. This recurrent variant seems to have a regional importance with a likely founder effect.ConclusionsThis report adds evidence to the pathogenicity of AIPL1 c.487C>T meriting its conclusive annotation as a recurrent pathogenic variant. This variant is particularly relevant to the middle-eastern and northeast African regions.

scholarly journals Case Report: Investigation and molecular genetic diagnosis of familial hypomagnesaemia: a case report

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 666
Author(s):  
Jamie Willows ◽  
Maryam Al Badi ◽  
Chloe Richardson ◽  
Noel Edwards ◽  
Sarah Rice ◽  
...  
Keyword(s):  
Case Report ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Consanguineous Family ◽  
Affected Child ◽  
Whole Exome ◽  
The Family ◽  
Domain Interactions ◽  
Molecular Genetic Diagnosis

Genetic mutations causing familial hypomagnesaemia syndromes are well-recognised.  Affected patients can present with severe symptoms of hypomagnesaemia, such as seizures or cardiac arrhythmia.  We report an affected child, from a consanguineous family, who presented in the first weeks of life with seizures secondary to hypomagnesaemia, without other associated clinical features.  We performed whole exome sequencing in the affected child and segregation analysis within the family, which revealed a novel homozygous missense mutation in TRPM6, which was confirmed as a heterozygous allele in both parents and two younger siblings who had transient hypomagnesaemia. Using in silico modelling, we provide evidence that the missense variant p.(K1098E) in TRPM6 is pathogenic, as it disrupts stabilising TRP domain interactions. Management of familial hypomagnesaemia relies on prompt recognition, early magnesium replacement and lifelong monitoring.

scholarly journals Identification of an unknown frameshift variant of NOG in a Han Chinese family with proximal symphalangism

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Zhuang-Zhuang Yuan ◽  
Fang Yu ◽  
Jie-Yuan Jin ◽  
Zi-Jun Jiao ◽  
Ju-Yu Tang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Conductive Hearing Loss ◽  
Genetic Diagnosis ◽  
Chinese Patient ◽  
Chinese Family ◽  
Autosomal Dominant Disorder ◽  
Genetic Lesion ◽  
Whole Exome ◽  
The Family ◽  
Conductive Hearing

Abstract Proximal symphalangism (SYM1) is an autosomal dominant disorder manifested by ankylosis of the proximal interphalangeal joints of fingers, carpal and tarsal bone fusion, and conductive hearing loss in some cases. Herein, we clinically diagnosed a Chinese patient with fusions of the bilateral proximal interphalangeal joints in the 2–5 digits without conductive hearing loss. Family history investigation revealed that his mother and grandfather also suffered from SYM1. Whole exome sequencing was performed to detect the genetic lesion of the family. The candidate gene variants were validated by Sanger sequencing. By data filtering, co-segregation analysis and bioinformatics analysis, we highly suspected that an unknown heterozygous frameshift variant (c.635_636insG, p.Q213Pfs*57) in NOG was responsible for the SYM1 in the family. This variant was predicted to be deleterious and resulted in a prolonged protein. This finding broadened the spectrum of NOG mutations associated with SYM1 and contributed to genetic diagnosis and counseling of families with SYM1.

scholarly journals Pathogenicity Reclassification of RPE65 Missense Variants Related to Leber Congenital Amaurosis and Early-Onset Retinal Dystrophy

Genes ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 24 ◽  
Author(s):  
Fabiana Motta ◽  
Renan Martin ◽  
Fernanda Porto ◽  
Elizabeth Wohler ◽  
Rosane Resende ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Early Onset ◽  
Retinal Dystrophy ◽  
Low Frequency ◽  
Sequencing Data ◽  
Leber Congenital Amaurosis ◽  
Missense Variants ◽  
Inherited Retinal Dystrophies ◽  
Inherited Retinal Dystrophy ◽  
Uncertain Significance

A challenge in molecular diagnosis and genetic counseling is the interpretation of variants of uncertain significance. Proper pathogenicity classification of new variants is important for the conclusion of molecular diagnosis and the medical management of patient treatments. The purpose of this study was to reclassify two RPE65 missense variants, c.247T>C (p.Phe83Leu) and c.560G>A (p.Gly187Glu), found in Brazilian families. To achieve this aim, we reviewed the sequencing data of a 224-gene retinopathy panel from 556 patients (513 families) with inherited retinal dystrophies. Five patients with p.Phe83Leu and seven with p.Gly187Glu were selected and their families investigated. To comprehend the pathogenicity of these variants, we evaluated them based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Initially, these RPE65 variants met only three pathogenic criteria: (i) absence or low frequency in the population, (ii) several missense pathogenic RPE65 variants, and (iii) 15 out of 16 lines of computational evidence supporting them as damaging, which together allowed the variants to be classified as uncertain significance. Two other pieces of evidence were accepted after further analysis of these Brazilian families: (i) p.Phe83Leu and p.Gly187Glu segregate with childhood retinal dystrophy within families, and (ii) their prevalence in Leber congenital amaurosis (LCA)/early-onset retinal dystrophy (EORD) patients can be considered higher than in other inherited retinal dystrophy patients. Therefore, these variants can now be classified as likely pathogenic according to ACMG/AMP classification guidelines.

scholarly journals Myoclonic status epilepticus and cerebellar hypoplasia associated with a novel variant in the GRIA3 gene

Neurogenetics ◽  
2021 ◽  
Author(s):  
Berardo Rinaldi ◽  
Yu-Han Ge ◽  
Elena Freri ◽  
Arianna Tucci ◽  
Tiziana Granata ◽  
...  
Keyword(s):  
Causative Role ◽  
Cerebellar Syndrome ◽  
Pathogenic Variants ◽  
Healthy Mother ◽  
Whole Exome ◽  
The Family ◽  
Novel Variant ◽  
Gene Maps ◽  
Index Subject

AbstractAMPA-type glutamate receptors (AMPARs) are postsynaptic ionotropic receptors which mediate fast excitatory currents. AMPARs have a heterotetrameric structure, variably composed by the four subunits GluA1-4 which are encoded by genes GRIA1-4. Increasing evidence support the role of pathogenic variants in GRIA1-4 genes as causative for syndromic intellectual disability (ID). We report an Italian pedigree where some male individuals share ID, seizures and facial dysmorphisms. The index subject was referred for severe ID, myoclonic seizures, cerebellar signs and short stature. Whole exome sequencing identified a novel variant in GRIA3, c.2360A > G, p.(Glu787Gly). The GRIA3 gene maps to chromosome Xq25 and the c.2360A > G variant was transmitted by his healthy mother. Subsequent analysis in the family showed a segregation pattern compatible with the causative role of this variant, further supported by preliminary functional insights. We provide a detailed description of the clinical evolution of the index subjects and stress the relevance of myoclonic seizures and cerebellar syndrome as cardinal features of his presentation.

“ There is No Cure for Stargardt’s”: The Prognosis and Rehabilitation of a Patient with Genetically Confirmed Abca 4 Mutations

2020 ◽  
pp. 237-242
Keyword(s):  
Gene Therapy ◽  
Genetic Counseling ◽  
Case Report ◽  
Autosomal Recessive ◽  
Retinal Dystrophy ◽  
Macular Dystrophy ◽  
African American Female ◽  
Abca4 Gene ◽  
Inherited Retinal Dystrophy ◽  
Comprehensive Rehabilitation

Background: Stargardt’s macular dystrophy is an autosomal recessive inherited retinal dystrophy associated with mutation in the ABCA4 gene. Although there are no current FDA approved treatments or cures for patients with Stargardt’s macular dystrophy, current research avenues include nutritional supplementation, drug therapies, and gene therapy. Case Report: A 58 year old African American female presents with suspected Stargardt’s with visual reports for comprehensive rehabilitation, including magnification assessment and genetic counseling of a patient with Stargardt’s macular dystrophy. Conclusion: Genetic testing provides insight to the phenotype and magnification determination provides significant rehabilitation to these individuals.

Chronic untreated retinal detachment in a patient with choroideremia provides insight into the disease process and potential therapy

2021 ◽  
pp. 112067212199472
Author(s):  
Maria Pilar Martin-Gutierrez ◽  
Thomas MW Buckley ◽  
Robert E MacLaren
Keyword(s):  
Gene Therapy ◽  
Retinal Detachment ◽  
Rhegmatogenous Retinal Detachment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Dystrophy ◽  
Disease Process ◽  
Peripheral Retina ◽  
Inherited Retinal Dystrophy ◽  
Insight Into

Aim: We present the case of a 72-year-old male with advanced choroideremia and a left chronic rhegmatogenous retinal detachment, which to our knowledge is the first formal report of a retinal detachment in this disease. Background: Choroideremia is a rare X-linked inherited retinal dystrophy, caused by mutations in the CHM gene which encodes Rab escort protein 1 (REP1), and affected males typically experience a progressive centripetal loss of vision. The disease pathology is caused by a primary retinal pigment epithelium degeneration, which leads to secondary loss of photoreceptors and choriocapillaris. This in turn leads to fusion of the degenerate outer retinal layers resulting in a retinopexy that is known to make subretinal gene therapy particularly challenging in these patients. Conclusion: Although retinal gene therapy is commonly targeted to the macular area in choroideremia, the observation of a rhegmatogenous retinal detachment indicates that the peripheral retina may not fuse with the residual choroid as occurs in the equatorial and macular regions. If this hypothesis is correct, targeting gene therapy to the retinal periphery even in advanced cases may be feasible and could potentially be used to preserve navigational vision.

scholarly journals Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

2021 ◽  
pp. bjophthalmol-2020-318483
Author(s):  
Malena Daich Varela ◽  
Thales Antonio Cabral de Guimaraes ◽  
Michalis Georgiou ◽  
Michel Michaelides
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Early Onset ◽  
Viral Vectors ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Dystrophy ◽  
European Medicines Agency ◽  
Current Management ◽  
Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and highlight the clinical trials that are on-going and planned. RPE65-related LCA pivotal trials, which culminated in the first Food and Drug Administration-approved and European Medicines Agency-approved ocular gene therapy, have paved the way for a new era of genetic treatments in ophthalmology. At present, multiple clinical trials are available worldwide applying different techniques, aiming to achieve better outcomes and include more genes and variants. Genetic therapy is not only implementing gene supplementation by the use of adeno-associated viral vectors, but also clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene editing and post-transcriptional regulation through antisense oligonucleotides. Pharmacological approaches intending to decrease photoreceptor degeneration by supplementing 11-cis-retinal and cell therapy’s aim to replace the retinal pigment epithelium, providing a trophic and metabolic retinal structure, are also under investigation. Furthermore, optoelectric devices and optogenetics are also an option for patients with residual visual pathway. After more than 10 years since the first patient with LCA received gene therapy, we also discuss future challenges, such as the overlap between different techniques and the long-term durability of efficacy. The next 5 years are likely to be key to whether genetic therapies will achieve their full promise, and whether stem cell/cellular therapies will break through into clinical trial evaluation.

scholarly journals Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood–Onset Retinal Dystrophy

Ophthalmology ◽  
2016 ◽  
Vol 123 (7) ◽  
pp. 1606-1620 ◽  
Author(s):  
Richard G. Weleber ◽  
Mark E. Pennesi ◽  
David J. Wilson ◽  
Shalesh Kaushal ◽  
Laura R. Erker ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Early Childhood ◽  
Retinal Dystrophy ◽  
Childhood Onset ◽  
Leber Congenital Amaurosis
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