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Hearing Disorders: HELP
Articles by Polona Le Quesne Stabej
Based on 4 articles published since 2010
(Why 4 articles?)

Between 2010 and 2020, Polona Le Quesne Stabej wrote the following 4 articles about Hearing Disorders.
+ Citations + Abstracts
1 Article An example of the utility of genomic analysis for fast and accurate clinical diagnosis of complex rare phenotypes. 2017

Le Quesne Stabej, Polona / James, Chela / Ocaka, Louise / Tekman, Mehmet / Grunewald, Stephanie / Clement, Emma / Stanescu, Horia C / Kleta, Robert / Morrogh, Deborah / Calder, Alistair / Williams, Hywel J / Bitner-Glindzicz, Maria. ·Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. · Division of Medicine, UCL, London, UK. · Department of Paediatric Metabolic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. · North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. · North East Thames Regional Genetics Laboratory, London, UK. · Radiology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. · Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. maria.bitner@ucl.ac.uk. ·Orphanet J Rare Dis · Pubmed #28173822.

ABSTRACT: BACKGROUND: We describe molecular diagnosis in a complex consanguineous family: four offspring presented with combinations of three distinctive phenotypes; non-syndromic hearing loss (NSHL), an unusual skeletal phenotype comprising multiple fractures, cranial abnormalities and diaphyseal expansion, and significant developmental delay with microcephaly. We performed Chromosomal Microarray Analysis on the offspring with either the skeletal or developmental delay phenotypes, and linkage analysis and whole exome sequencing (WES) on all four children, parents and maternal aunt. RESULTS: Chromosomal microarray and FISH analysis identified a de novo unbalanced translocation as a cause of the microcephaly and severe developmental delay. WES identified a NSHL-causing splice variant in an autosomal recessive deafness gene PDZD7 which resided in a linkage region and affected three of the children. In the two children diagnosed with an unusual skeletal phenotype, WES eventually disclosed a heterozygous COL1A1 variant which affects C-propetide cleavage site of COL1. The variant was inherited from an apparently unaffected mosaic father in an autosomal dominant fashion. After the discovery of the COL1A1 variant, the skeletal phenotype was diagnosed as a high bone mass form of osteogenesis imperfecta. CONCLUSIONS: Next generation sequencing offers an unbiased approach to molecular genetic diagnosis in highly heterogeneous and poorly characterised disorders and enables early diagnosis as well as detection of mosaicism.

2 Article Natural history and retinal structure in patients with Usher syndrome type 1 owing to MYO7A mutation. 2014

Lenassi, Eva / Saihan, Zubin / Cipriani, Valentina / Le Quesne Stabej, Polona / Moore, Anthony T / Luxon, Linda M / Bitner-Glindzicz, Maria / Webster, Andrew R. ·UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom; Eye Hospital, University Medical Centre, Ljubljana, Slovenia. · Moorfields Eye Hospital, London, United Kingdom. · UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom. · UCL Institute of Child Health, London, United Kingdom. · UCL Ear Institute, London, United Kingdom. · UCL Institute of Ophthalmology, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom. Electronic address: andrew.webster@ucl.ac.uk. ·Ophthalmology · Pubmed #24199935.

ABSTRACT: PURPOSE: To evaluate the phenotypic variability and natural history of ocular disease in a cohort of 28 individuals with MYO7A-related disease. Mutations in the MYO7A gene are the most common cause of Usher syndrome type 1, characterized by profound congenital deafness, vestibular arreflexia, and progressive retinal degeneration. DESIGN: Retrospective case series. PARTICIPANTS: Twenty-eight patients from 26 families (age range, 3-65 years; median, 32) with 2 likely disease-causing variants in MYO7A. METHODS: Clinical investigations included fundus photography, optical coherence tomography, fundus autofluorescence (FAF) imaging, and audiologic and vestibular assessments. Longitudinal visual acuity and FAF data (over a 3-year period) were available for 20 and 10 study subjects, respectively. MAIN OUTCOME MEASURES: Clinical, structural, and functional characteristics. RESULTS: All patients with MYO7A mutations presented with features consistent with Usher type 1. The median visual acuity for the cohort was 0.39 logarithm of the minimum angle of resolution (logMAR; range, 0.0-2.7) and visual acuity in logMAR correlated with age (Spearman's rank correlation coefficient, r = 0.71; P<0.0001). Survival analysis revealed that acuity ≤ 0.22 logMAR was maintained in 50% of studied subjects until age 33.9; legal blindness based on loss of acuity (≥ 1.00 logMAR) or loss of field (≤ 20°) was reached at a median age of 40.6 years. Three distinct patterns were observed on FAF imaging: 13 of 22 patients tested had relatively preserved foveal autofluorescence surrounded by a ring of high density, 4 of 22 had increased signal in the fovea with no obvious hyperautofluorescent ring, and 5 of 22 had widespread hypoautofluorescence corresponding to retinal pigment epithelial atrophy. Despite a number of cases presenting with a milder phenotype, there seemed to be no obvious genotype-phenotype correlation. CONCLUSIONS: MYO7A-related ocular disease is variable. Central vision typically remains preserved at least until the third decade of life, with 50% of affected individuals reaching legal blindness by 40 years of age. Distinct phenotypic subsets were identified on FAF imaging. A specific allele, previously reported in nonsyndromic deafness, may be associated with a mild retinopathy.

3 Article Screening for duplications, deletions and a common intronic mutation detects 35% of second mutations in patients with USH2A monoallelic mutations on Sanger sequencing. 2013

Steele-Stallard, Heather B / Le Quesne Stabej, Polona / Lenassi, Eva / Luxon, Linda M / Claustres, Mireille / Roux, Anne-Francoise / Webster, Andrew R / Bitner-Glindzicz, Maria. ·UCL Institute of Child Health, London, UK. ·Orphanet J Rare Dis · Pubmed #23924366.

ABSTRACT: BACKGROUND: Usher Syndrome is the leading cause of inherited deaf-blindness. It is divided into three subtypes, of which the most common is Usher type 2, and the USH2A gene accounts for 75-80% of cases. Despite recent sequencing strategies, in our cohort a significant proportion of individuals with Usher type 2 have just one heterozygous disease-causing mutation in USH2A, or no convincing disease-causing mutations across nine Usher genes. The purpose of this study was to improve the molecular diagnosis in these families by screening USH2A for duplications, heterozygous deletions and a common pathogenic deep intronic variant USH2A: c.7595-2144A>G. METHODS: Forty-nine Usher type 2 or atypical Usher families who had missing mutations (mono-allelic USH2A or no mutations following Sanger sequencing of nine Usher genes) were screened for duplications/deletions using the USH2A SALSA MLPA reagent kit (MRC-Holland). Identification of USH2A: c.7595-2144A>G was achieved by Sanger sequencing. Mutations were confirmed by a combination of reverse transcription PCR using RNA extracted from nasal epithelial cells or fibroblasts, and by array comparative genomic hybridisation with sequencing across the genomic breakpoints. RESULTS: Eight mutations were identified in 23 Usher type 2 families (35%) with one previously identified heterozygous disease-causing mutation in USH2A. These consisted of five heterozygous deletions, one duplication, and two heterozygous instances of the pathogenic variant USH2A: c.7595-2144A>G. No variants were found in the 15 Usher type 2 families with no previously identified disease-causing mutations. In 11 atypical families, none of whom had any previously identified convincing disease-causing mutations, the mutation USH2A: c.7595-2144A>G was identified in a heterozygous state in one family. All five deletions and the heterozygous duplication we report here are novel. This is the first time that a duplication in USH2A has been reported as a cause of Usher syndrome. CONCLUSIONS: We found that 8 of 23 (35%) of 'missing' mutations in Usher type 2 probands with only a single heterozygous USH2A mutation detected with Sanger sequencing could be attributed to deletions, duplications or a pathogenic deep intronic variant. Future mutation detection strategies and genetic counselling will need to take into account the prevalence of these types of mutations in order to provide a more comprehensive diagnostic service.

4 Article Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. 2012

Le Quesne Stabej, Polona / Saihan, Zubin / Rangesh, Nell / Steele-Stallard, Heather B / Ambrose, John / Coffey, Alison / Emmerson, Jenny / Haralambous, Elene / Hughes, Yasmin / Steel, Karen P / Luxon, Linda M / Webster, Andrew R / Bitner-Glindzicz, Maria. ·Clinical and Molecular Genetics, Institute of Child Health, UCL, London, UK. ·J Med Genet · Pubmed #22135276.

ABSTRACT: BACKGROUND: Usher syndrome (USH) is an autosomal recessive disorder comprising retinitis pigmentosa, hearing loss and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous with three distinctive clinical types (I-III) and nine Usher genes identified. This study is a comprehensive clinical and genetic analysis of 172 Usher patients and evaluates the contribution of digenic inheritance. METHODS: The genes MYO7A, USH1C, CDH23, PCDH15, USH1G, USH2A, GPR98, WHRN, CLRN1 and the candidate gene SLC4A7 were sequenced in 172 UK Usher patients, regardless of clinical type. RESULTS: No subject had definite mutations (nonsense, frameshift or consensus splice site mutations) in two different USH genes. Novel missense variants were classified UV1-4 (unclassified variant): UV4 is 'probably pathogenic', based on control frequency <0.23%, identification in trans to a pathogenic/probably pathogenic mutation and segregation with USH in only one family; and UV3 ('likely pathogenic') as above, but no information on phase. Overall 79% of identified pathogenic/UV4/UV3 variants were truncating and 21% were missense changes. MYO7A accounted for 53.2%, and USH1C for 14.9% of USH1 families (USH1C:c.496+1G>A being the most common USH1 mutation in the cohort). USH2A was responsible for 79.3% of USH2 families and GPR98 for only 6.6%. No mutations were found in USH1G, WHRN or SLC4A7. CONCLUSIONS: One or two pathogenic/likely pathogenic variants were identified in 86% of cases. No convincing cases of digenic inheritance were found. It is concluded that digenic inheritance does not make a significant contribution to Usher syndrome; the observation of multiple variants in different genes is likely to reflect polymorphic variation, rather than digenic effects.