scholarly journals Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants in PC and analysis of the genotype–phenotype correlation

2019 ◽  
Vol 40 (6) ◽  
pp. 816-827 ◽  
Author(s):  
Emanuele G. Coci ◽  
Vytautas Gapsys ◽  
Natasha Shur ◽  
Yoon Shin‐Podskarbi ◽  
Bert L. Groot ◽  
...  
Keyword(s):  
Pyruvate Carboxylase ◽  
Type A ◽  
Phenotype Correlation ◽  
Pathogenic Variants ◽  
Pyruvate Carboxylase Deficiency ◽  
Genotype Phenotype Correlation ◽  
Type C ◽  
Deficiency Type

scholarly journals Genotype-phenotype correlation analysis and therapeutic development using a patient stem cell-derived disease model of Wolfram syndrome

2021 ◽  
Author(s):  
Rie Asada Kitamura ◽  
Kristina Maxwell ◽  
Wenjuan Ye ◽  
Kelly Kries ◽  
Cris Brown ◽  
...  
Keyword(s):  
Stem Cell ◽  
Correlation Analysis ◽  
Combination Treatment ◽  
Disease Model ◽  
Wolfram Syndrome ◽  
Phenotype Correlation ◽  
Chemical Chaperones ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation ◽  
Therapeutic Development

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant which is highly prevalent in the Ashkenazi-Jewish population. Clinical investigation indicates that subjects carrying the homozygous WFS1 c.1672C>T, p.R558C variant show mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C is more stable compared to the other known recessive pathogenic variants associated with Wolfram syndrome. Stem cell-derived islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulates genotype-related Wolfram phenotypes, which are milder than those of SC-islets with compound heterozygous WFS1 c.1672C>T (p.R558C), c.2654C>T (p.P885L). Enhancing residual WFS1 function by a combination treatment of chemical chaperones, sodium 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), mitigates detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and restored SC-islet function. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient stem cell-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.

scholarly journals Genotype-phenotype correlation in fibrous dysplasia/McCune-Albright syndrome

2021 ◽  
Author(s):  
Maria Zhadina ◽  
Kelly L Roszko ◽  
Raya E S Geels ◽  
Luis F de Castro ◽  
Michael T Collins ◽  
...  
Keyword(s):  
Fibrous Dysplasia ◽  
Phenotype Correlation ◽  
Cross Sectional ◽  
Mccune Albright Syndrome ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation ◽  
Large Patient ◽  
Pancreatic Involvement ◽  
Albright Syndrome ◽  
Mccune Albright

Abstract Context Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder resulting in fractures, pain, and disability. There are no targeted or effective therapies to alter the disease course. Disease arises from somatic gain-of-function variants at the R201 codon in GNAS, replacing arginine by either cysteine or histidine. The relative pathogenicity of these variants is not fully understood. Objective 1) To determine whether the most common GNAS variants (R201C and R201H) are associated with a specific clinical phenotype, and 2) to determine the prevalence of the most common GNAS variants in a large patient cohort. Design Retrospective cross-sectional analysis Main Outcome Measures Correlation between genotype and phenotype characterized by clinical, biochemical, and radiographic data. Results Sixty-one subjects were genotyped using DNA extracted from tissue or circulating cell-free DNA. Twenty-two subjects (36.1%) had the R201C variant, and 39 (63.9%) had the R201H variant. FD skeletal disease burden, hypophosphatemia prevalence, fracture incidence, and ambulation status were similar between the two groups. There was no difference in the prevalence of endocrinopathies, ultrasonographic gonadal or thyroid abnormalities, or pancreatic involvement. There was a non-significant association of cancer with the R201H variant. Conclusion There is no clear genotype-phenotype correlation in patients with the most common FD/MAS pathogenic variants. The predominance of the R201H variant observed in our cohort and reported in the literature indicates it is likely responsible for a larger burden of disease in the overall population of patients with FD/MAS, which may have important implications for future development of targeted therapies.

scholarly journals Phenotypic Profiling in Subjects Heterozygous for 1 of 2 Rare Variants in the Hypophosphatasia Gene (ALPL)

2020 ◽  
Vol 4 (8) ◽  
Author(s):  
Daniel R Tilden ◽  
Jonathan H Sheehan ◽  
John H Newman ◽  
Jens Meiler ◽  
John A Capra ◽  
...  
Keyword(s):  
Medical Records ◽  
Rare Variants ◽  
Serum Alkaline Phosphatase ◽  
Clinical Care ◽  
Test Results ◽  
Phenotype Correlation ◽  
Clinical Phenotypes ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation ◽  
Genetic Test Results

Abstract Context Hypophosphatasia (HPP) is a syndrome marked by low serum alkaline phosphatase (AlkP) activity as well as musculoskeletal and/or dental disease. While the majority of subjects with HPP carry a pathogenic variant in the ALPL gene or its regulatory regions, individual pathogenic variants are often not tightly correlated with clinical symptomatology. We sought to better understand the genotype/phenotype correlation in HPP by examining the clinical and biochemical data of 37 subjects with 2 rare variants in ALPL. Methods Through BioVU, a DNA biobank that pairs individuals’ genetic information with their de-identified medical records, we identified subjects with 2 rare variants with distinct reported clinical phenotypes (p.D294A and p.T273M). We then performed a manual review of these subjects’ de-identified medical records along with computational modeling of protein structure to construct a genetic, biochemical and clinical phenotype for each subject and variant. Results Twenty subjects with the p.D294A variant and 17 with the p.T273M variant had sufficient data for analysis. Among subjects in our cohort with the p.D294A variant, 6 (30.0%) had both clinical bone disease and serum AlkP activity below 40 IU/L while 4 subjects (23.5%) with the p.T273M variant met the same criteria despite the distinct clinical phenotypes of these variants. Conclusions Given the loose genotype/phenotype correlation in HPP seen in our cohort, clinical context is crucial for the interpretation of genetic test results to guide clinical care in this population. Otherwise, over- or under-diagnosis may occur, resulting in misidentification of those who may benefit from additional screening and perhaps pharmacologic intervention.

Pathogenic/likely pathogenic variants in the SHOX, GHR and IGFALS genes among Indian children with idiopathic short stature

2020 ◽  
Vol 33 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Anil Kumar ◽  
Vandana Jain ◽  
Madhumita Roy Chowdhury ◽  
Manoj Kumar ◽  
Punit Kaur ◽  
...  
Keyword(s):  
Growth Factor ◽  
Short Stature ◽  
Serum Insulin ◽  
Significant Proportion ◽  
Idiopathic Short Stature ◽  
Insulin Like Growth Factor ◽  
Phenotype Correlation ◽  
Indian Children ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation

AbstractBackgroundOur objective was to estimate the prevalence of pathogenic/likely pathogenic variants in the SHOX, GHR, and IGFALS genes among Indian children with idiopathic short stature (ISS), and assess the genotype-phenotype correlation.MethodsWe recruited 61 children with short stature, who were born appropriate for gestational age, had no obvious dysmorphism or disproportion, and in whom step-wise investigative work-up (including provocative growth hormone test) was normal. Multiplex ligation-dependent probe amplification was undertaken for identifying deletions/duplications in the SHOX gene. Bidirectional sequencing was performed for identifying variants in the SHOX and GHR genes in all, and for the IGFALS gene in those with serum insulin-like growth factor-1 (IGF-1) <−1 standard deviation. The genotype-phenotype correlation was studied.ResultsFour children (6.5%) had pathogenic heterozygous variants in the SHOX gene, with one child each having duplication of exon 5, splice site point variant c.278-1G > C in exon 3, partial deletion and complete deletion. None of the patients had pathogenic variants in the GHR gene. Of the 39 patients in whom the IGFALS gene was sequenced, novel heterozygous likely pathogenic variants were found in two children. One had the frameshift variant c.764_765insT, p.A265Gfs*114. The second had the missense variant c.1793G > A, p.R598H predicted by MutationTaster as ‘disease causing’, and indicated by the protein-modelling study as having compromised binding with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) due to altered conformation of the interacting loop.ConclusionsPathogenic variants in the SHOX and IGFALS genes account for a significant proportion of Indian children with ISS. Further molecular studies using next generation sequencing are needed to gain insight into pathophysiological mechanisms and effective treatment strategies for ISS.

scholarly journals Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy

2009 ◽  
Vol 30 (10) ◽  
pp. E936-E945 ◽  
Author(s):  
Martina Cesani ◽  
Alessia Capotondo ◽  
Tiziana Plati ◽  
Lucia Sergi Sergi ◽  
Francesca Fumagalli ◽  
...  
Keyword(s):  
Metachromatic Leukodystrophy ◽  
Gene Mutations ◽  
Arylsulfatase A ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation

Clinical and molecular characterization of Brazilian families with von Hippel-Lindau disease: a need for delineating genotype-phenotype correlation

2010 ◽  
Vol 9 (4) ◽  
pp. 635-642 ◽  
Author(s):  
Israel Gomy ◽  
Greice Andreotti Molfetta ◽  
Ester de Andrade Barreto ◽  
Cristiane Ayres Ferreira ◽  
Dalila Luciola Zanette ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Phenotype Correlation ◽  
Von Hippel Lindau ◽  
Genotype Phenotype Correlation ◽  
Von Hippel Lindau Disease

scholarly journals Characterization of KPC-Encoding Plasmids from Enterobacteriaceae Isolated in a Czech Hospital

2017 ◽  
Vol 62 (3) ◽  
Author(s):  
Rudolf Kukla ◽  
Katerina Chudejova ◽  
Costas C. Papagiannitsis ◽  
Matej Medvecky ◽  
Katerina Habalova ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Type A ◽  
Type B ◽  
Content Type ◽  
Type C ◽  
Derivatives Of

ABSTRACT Ten Enterobacteriaceae isolates collected in a Czech hospital carried bla KPC -positive plasmids of different sizes (∼30, ∼45, and ∼80 kb). Sequencing revealed three types of plasmids (A to C) with the Tn 4401a transposon. Type A plasmids comprised an IncR backbone and a KPC-2-encoding multidrug resistance (MDR) region. Type B plasmids were derivatives of type A plasmids carrying an IncN3-like segment, while type C plasmids were IncP6 plasmids sharing the same KPC-2-encoding MDR region with type A and B plasmids.

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