scholarly journals USH2A gene variants cause Keratoconus and Usher syndrome phenotypes in Pakistani families

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Asif Naveed Ahmed ◽  
Raheel Tahir ◽  
Niamat Khan ◽  
Mushtaq Ahmad ◽  
Muhammad Dawood ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Usher Syndrome ◽  
Retinal Dystrophy ◽  
Significant Proportion ◽  
Missense Variant ◽  
Causative Role ◽  
Pakistani Family ◽  
Inherited Retinal Dystrophy ◽  
Novel Variant

Abstract Background Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, affecting approximately 1 in 4000 individuals worldwide. The most common form of syndromic RP is Usher syndrome (USH) accounting for approximately 20–30 % of RP cases. Mutations in the USH2A gene cause a significant proportion of recessive non-syndromic RP and USH type II (USH2). This study aimed to determine the causative role of the USH2A gene in autosomal recessive inherited ocular diseases and to establish genotype-phenotype correlation associated with USH2A variants. Methods We performed direct Sanger sequencing and co-segregation analysis of the USH2A gene to identify disease causing variants in a non-syndromic RP family, two USH2 families and two Keratoconus (KC) families. Results Disease causing variants in the USH2A gene were identified in two families displayed KC and USH2 phenotypes. A novel variant c.4029T > G, p.Asn1343Lys in the USH2A gene was detected in a Pakistani family with KC phenotype. In addition, a missense variant (c.7334 C > T, p. Ser2445Phe) in the USH2A gene was found segregating in another Pakistani family with USH2 phenotype. Homozygosity of identified missense USH2A variants was found associated with autosomal recessive inherited KC and USH2 phenotypes in investigated families. These variants were not detected in ethnically matched healthy controls. Moreover, the USH2A variants were predicted to be deleterious or potentially disease causing by PolyPhen-2, PROVEAN and SIFT. Conclusions This study provided first evidence for association of a novel USH2A variant with KC phenotype in a Pakistani family as well as established the phenotype-genotype correlation of a USH2A variant (c.7334 C > T, p. Ser2445Phe) with USH2 phenotype in another Pakistani family. The phenotype-genotype correlations established in present study may improve clinical diagnosis of affected individuals for better management and counseling.

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

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

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

scholarly journals Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder

2021 ◽  
Author(s):  
Francesca Mattioli ◽  
Hossein Darvish ◽  
Sohail Aziz Paracha ◽  
Abbas Tafakhori ◽  
Saghar Ghasemi Firouzabadi ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Autosomal Recessive ◽  
High Throughput Sequencing ◽  
Neurodevelopmental Disorder ◽  
Behavioral Changes ◽  
Causative Role ◽  
Speech Impairment ◽  
Lipid Flippase

Intellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes. In this report we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a-/- mouse model showed behavioral changes.

scholarly journals Expanding the clinical and genetic spectrum of Heimler syndrome

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Feng-Juan Gao ◽  
Fang-Yuan Hu ◽  
Ping Xu ◽  
Yu-He Qi ◽  
Jian-Kang Li ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Clinical Practice ◽  
Usher Syndrome ◽  
Retinal Dystrophy ◽  
Missense Variant ◽  
Pathogenic Mutation ◽  
Genetic Characteristics ◽  
Aaa Atpase ◽  
Systemic Disorder ◽  
Generation Sequencing

Abstract Background Heimler syndrome (HS) is a rare hereditary systemic disorder, partial clinically overlapping with Usher syndrome. So far, our knowledge of HS is very limited, many cases are misdiagnosed or may not even be diagnosed at all. This study aimed to analyze the clinical and genetic characteristics of HS, and to evaluate potential phenotype–genotype correlations. Results Two HS cases caused by PEX1 mutations were identified, and a novel likely pathogenic mutation, PEX1 c.895_896insTATA, was found. The main ophthalmic finding of the two patients was consistent with retinitis pigmentosa accompanied by cystoid macular edema, but short axial length and hyperopia were also observed as two previously unreported ocular phenotypes. Analysis of the literature showed that of the 29 HS patients previously reported, 12 had PEX6 mutations, 10 had PEX1 mutations, two had PEX26 mutations, and the remaining patients were not genetically tested. Three novel genotype–phenotype correlations were revealed from analysis of these patients. First, most genotypes of every HS patient include at least one missense variant; second, at least one mutation in PEX1 or PEX6 gene affects the AAA-ATPase region in every HS patient with retinal dystrophy, suggesting AAA-ATPase region is a hypermutable region in patients with a retinal dystrophy; third, there are no significant differences between PEX1-, PEX6-, and PEX26-associated phenotypes. Conclusion Next-generation sequencing is important for the diagnosis of HS. This study expands the clinical and genetic spectrum of HS, and provides additional insights into genotype–phenotype correlations, which is vital for accurate clinical practice, genetic counseling, and pathogenesis studies.

scholarly journals Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Francesca Mattioli ◽  
Hossein Darvish ◽  
Sohail Aziz Paracha ◽  
Abbas Tafakhori ◽  
Saghar Ghasemi Firouzabadi ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Autosomal Recessive ◽  
High Throughput Sequencing ◽  
Neurodevelopmental Disorder ◽  
Behavioral Changes ◽  
Causative Role ◽  
Speech Impairment ◽  
Lipid Flippase

AbstractIntellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes. In this report, we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a−/− mouse model showed behavioral changes.

Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss

2019 ◽  
Vol 96 (6) ◽  
pp. 575-578
Author(s):  
Oscar Diaz‐Horta ◽  
Guney Bademci ◽  
Suna Tokgoz‐Yilmaz ◽  
Shengru Guo ◽  
Faraz Zafeer ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Dominant ◽  
Causative Role ◽  
Novel Variant

“ 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.

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.

Update regarding anemia in heart failure

Medic ro ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. 8-13
Author(s):  
Roxana Marcela Sânpălean ◽  
Dorina Nastasia Petra
Keyword(s):  
Heart Failure ◽  
Iron Deficiency ◽  
Multidisciplinary Team ◽  
Significant Proportion ◽  
Life Quality ◽  
Lower Number ◽  
Nutritional Deficiencies ◽  
Cardiac Morbidity ◽  
Appropriate Treatment

Heart failure (HF) is a burden for the healthcare system. The incidence will increase significantly due to the aging of po­pu­la­tion, which is associated with multiple comorbidities. Ane­mia and iron deficiency are common in patients with HF, their etiology being often multifactorial. The screening for anemia and iron deficiency is recommended as soon as pos­si­ble. There are often no targeted investigations, therefore a significant proportion of cases are underdiagnosed. The ma­nagement of patients may focus on identifying and correcting the cause. Anemia can occur due to nutritional deficiencies, infla­m­mation, renal failure, bone marrow dysfunction, neuro­hor­mo­nal activity, treatment and hemodilution. The appropriate the­ra­py for the patients with anemia and HF will contribute to the improvement of life quality. The only recommended iron product is ferric carboxymalose administered by in­tra­venous infusion. Under the appropriate treatment, the pa­tients showed an increase in effort tolerance, with an im­prove­ment in symptomatology and a lower number of hos­pi­ta­li­za­tion days. The management of these cases is handled by a multidisciplinary team consisting of a general prac­ti­tio­ner, a cardiologist and other specialists if the patient has other comorbidities. The role of the general practitioner is essential, as he can perform proper screening, prevention and management, developed by a multidisciplinary team, in order to reduce the cardiac morbidity and mortality.  

Papillon-Lefevre Syndrome: Challenge for Periodontal Management

2019 ◽  
Vol 3 (2) ◽  
pp. 84-86
Author(s):  
Krishna Prasad Lamichhane ◽  
Shaili Pradhan ◽  
Ranjita Shreshta Gorkhali ◽  
Pramod Kumar Koirala
Keyword(s):  
Significant Role ◽  
Autosomal Recessive ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Genetic Mutations ◽  
Rare Autosomal Recessive Disorder ◽  
Diagnosis And Management ◽  
Periodontal Destruction ◽  
Palmoplantar Keratosis

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder associated with rapidly progressing periodontitis leading to premature loss of deciduous and permanent dentition and diffuse palmoplantar keratosis. Immunologic alterations, genetic mutations, and role of bacteria are some aetiologic factors. Patients present with early periodontal destruction, so periodontists play a significant role in diagnosis and management. This paper reports a case of Papillon- Lefevre syndrome with its clinical manifestations and challenges for periodontal management which was diagnosed in dental department.

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