Clinical and genetic characteristics of sporadic adult-onset degenerative ataxia

Objective:To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations.Methods:The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing.Results:The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, p < 0.0001) and disease duration (0.22 ± 0.06 per additional year, p = 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, p = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made.Conclusions:Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort.ClinicalTrials.gov registration:NCT02701036.

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Leukodystrophies and Genetic Leukoencephalopathies in Children Specified by Exome Sequencing in an Expanded Gene Panel

Journal of Child Neurology ◽

10.1177/0883073820904294 ◽

2020 ◽

Vol 35 (7) ◽

pp. 433-441

Author(s):

Bindu Parayil Sankaran ◽

Madhu Nagappa ◽

Shwetha Chiplunkar ◽

Sonam Kothari ◽

Periyasamy Govindaraj ◽

...

Keyword(s):

Exome Sequencing ◽

Genetic Diagnosis ◽

Gene Panel ◽

Unknown Etiology ◽

Mri Findings ◽

Diagnostic Challenge ◽

Variants Of Unknown Significance ◽

Pathogenic Variants ◽

Genetic Features ◽

Biopsy Confirmation

The overlapping clinical and neuroimaging phenotypes of leukodystrophies pose a diagnostic challenge to both clinicians and researchers alike. Studies on the application of exome sequencing in the diagnosis of leukodystrophies are emerging. We used targeted gene panel sequencing of 6440 genes to investigate the genetic etiology in a cohort of 50 children with neuroimaging diagnosis of leukodystrophy/genetic leukoencephalopathy of unknown etiology. These 50 patients without a definite biochemical or genetic diagnosis were derived from a cohort of 88 patients seen during a 2.5-year period (2015 January-2017 June). Patients who had diagnosis by biochemical or biopsy confirmation (n = 17) and patients with incomplete data or lack of follow-up (n = 21) were excluded. Exome sequencing identified variants in 30 (60%) patients, which included pathogenic or likely pathogenic variants in 28 and variants of unknown significance in 2. Among the patients with pathogenic or likely pathogenic variants, classic leukodystrophies constituted 13 (26%) and genetic leukoencephalopathies 15 (30%). The clinical and magnetic resonance imaging (MRI) findings and genetic features of the identified disorders are discussed.

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Genotypes Predispose Phenotypes—Clinical Features and Genetic Spectrum of ABCA4-Associated Retinal Dystrophies

Genes ◽

10.3390/genes11121421 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1421

Author(s):

Yu-Chi Sung ◽

Chang-Hao Yang ◽

Chung-May Yang ◽

Chao-Wen Lin ◽

Ding-Siang Huang ◽

...

Keyword(s):

Visual Acuity ◽

Retinal Degeneration ◽

Medical Center ◽

Fundus Autofluorescence ◽

Genetic Diagnosis ◽

Common Disease ◽

Genetic Characteristics ◽

Retinal Dystrophies ◽

High Prevalence ◽

Abca4 Gene

The ABCA4 gene is one of the most common disease-causing genes of inherited retinal degeneration. In this study, we report different phenotypes of ABCA4-associated retinal dystrophies in the Taiwanese population, its clinical progression, and its relationship with genetic characteristics. Thirty-seven subjects were recruited and all patients underwent serial ophthalmic examinations at a single medical center. Fundus autofluorescence (FAF) images were quantified for clinical evaluation, and panel-based next-generation sequencing testing was performed for genetic diagnosis. Visual preservation, disease progression, and genotype–phenotype correlation were analyzed. In this cohort, ABCA4-associated retinal degeneration presented as Stargardt disease 1 (STGD1, 62.16%), retinitis pigmentosa (32.43%), and cone-rod dystrophy (5.41%). STGD1 could be further divided into central and dispersed types. In each phenotype, the lesion areas quantified by FAF increased with age (p < 0.01) and correlated with poorer visual acuity. However, three patients had the foveal sparing phenotype and had relatively preserved visual acuity. Forty-two ABCA4 variants were identified as disease-causing, with c.1804C>T (p.Arg602Trp) the most frequent (37.84%). Patients with a combination of severe/null variants could have more extensive phenotypes, such as arRP and dispersed STGD1. This is the first cohort study of ABCA4-associated retinal degeneration in Taiwan with wide spectrums of both genotypic and phenotypic characteristics. An extremely high prevalence of c.1804C>T, which has not been reported in East Asia before, was noted. The extensiveness of retinal involvement might be regarded as a spectrum of ABCA4-associated retinal dystrophies. Different types of genetic variations could lead to distinctive phenotypes, according to the coding impact of variants.

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P040 Highly Sensitivity and Fast Genetic Diagnosis by Mean of a Novel NGS-Based Resequencing Gene Panel Underlying SCLC Patients

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2018.10.063 ◽

2018 ◽

Vol 13 (12) ◽

pp. S1066

Author(s):

J. Wang ◽

L. Zhao ◽

X. Sun ◽

F. Zhou ◽

Y. Zhang ◽

...

Keyword(s):

Genetic Diagnosis ◽

Gene Panel

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FC 011KIDNEYNETWORK: USING KIDNEY DERIVED GENE EXPRESSION DATA TO PREDICT AND PRIORITIZE NOVEL GENES INVOLVED IN KIDNEY DISEASE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab131.001 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Floranne Boulogne ◽

Laura Claus ◽

Henry Wiersma ◽

Roy Oelen ◽

Floor Schukking ◽

...

Keyword(s):

Gene Expression ◽

Kidney Disease ◽

Candidate Gene ◽

Exome Sequencing ◽

Rna Sequencing ◽

Expression Patterns ◽

Genetic Diagnosis ◽

Specific Gene ◽

Sequencing Data ◽

Exome Sequencing Data

Abstract Background and Aims Genetic testing in patients with suspected hereditary kidney disease does not always reveal the genetic cause for the patient's disorder. Potentially pathogenic variants can reside in genes that are not known to be involved in kidney disease, which makes it difficult to prioritize and interpret the relevance of these variants. As such, there is a clear need for methods that predict the phenotypic consequences of gene expression in a way that is as unbiased as possible. To help identify candidate genes we have developed KidneyNetwork, in which tissue-specific expression is utilized to predict kidney-specific gene functions. Method We combined gene co-expression in 878 publicly available kidney RNA-sequencing samples with the co-expression of a multi-tissue RNA-sequencing dataset of 31,499 samples to build KidneyNetwork. The expression patterns were used to predict which genes have a kidney-related function, and which (disease) phenotypes might be caused when these genes are mutated. By integrating the information from the HPO database, in which known phenotypic consequences of disease genes are annotated, with the gene co-expression network we obtained prediction scores for each gene per HPO term. As proof of principle, we applied KidneyNetwork to prioritize variants in exome-sequencing data from 13 kidney disease patients without a genetic diagnosis. Results We assessed the prediction performance of KidneyNetwork by comparing it to GeneNetwork, a multi-tissue co-expression network we previously developed. In KidneyNetwork, we observe a significantly improved prediction accuracy of kidney-related HPO-terms, as well as an increase in the total number of significantly predicted kidney-related HPO-terms (figure 1). To examine its clinical utility, we applied KidneyNetwork to 13 patients with a suspected hereditary kidney disease without a genetic diagnosis. Based on the HPO terms “Renal cyst” and “Hepatic cysts”, combined with a list of potentially damaging variants in one of the undiagnosed patients with mild ADPKD/PCLD, we identified ALG6 as a new candidate gene. ALG6 bears a high resemblance to other genes implicated in this phenotype in recent years. Through the 100,000 Genomes Project and collaborators we identified three additional patients with kidney and/or liver cysts carrying a suspected deleterious variant in ALG6. Conclusion We present KidneyNetwork, a kidney specific co-expression network that accurately predicts what genes have kidney-specific functions and may result in kidney disease. Gene-phenotype associations of genes unknown for kidney-related phenotypes can be predicted by KidneyNetwork. We show the added value of KidneyNetwork by applying it to exome sequencing data of kidney disease patients without a molecular diagnosis and consequently we propose ALG6 as a promising candidate gene. KidneyNetwork can be applied to clinically unsolved kidney disease cases, but it can also be used by researchers to gain insight into individual genes to better understand kidney physiology and pathophysiology. Acknowledgments This research was made possible through access to the data and findings generated by the 100,000 Genomes Project; http://www.genomicsengland.co.uk.

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Early onset as a marker for disease severity in facioscapulohumeral muscular dystrophy

Neurology ◽

10.1212/wnl.0000000000006819 ◽

2018 ◽

Vol 92 (4) ◽

pp. e378-e385 ◽

Cited By ~ 8

Author(s):

Rianne J.M. Goselink ◽

Karlien Mul ◽

Caroline R. van Kernebeek ◽

Richard J.L.F. Lemmers ◽

Silvère M. van der Maarel ◽

...

Keyword(s):

Hearing Loss ◽

Muscular Dystrophy ◽

Disease Severity ◽

Muscle Weakness ◽

Early Onset ◽

Disease Duration ◽

Facioscapulohumeral Muscular Dystrophy ◽

Work Status ◽

Control Groups ◽

Genetic Characteristics

ObjectiveTo assess the relation between age at onset and disease severity in facioscapulohumeral muscular dystrophy (FSHD).MethodsIn this prospective cross-sectional study, we matched adult patients with FSHD with an early disease onset with 2 sex-matched FSHD control groups with a classic onset; the first group was age matched, and the second group was disease duration matched. Genetic characteristics, muscle performance, respiratory functioning, hearing loss, vision loss, epilepsy, educational level, and work status were compared with the 2 control groups.ResultsTwenty-eight patients with early-onset FSHD were age (n = 28) or duration (n = 27) matched with classic-onset patients. Patients with early-onset FSHD had more severe muscle weakness (mean FSHD clinical score 11 vs 5 in the age-matched and 9 in the duration-matched group, p < 0.05) and a higher frequency of wheelchair dependency (57%, 0%, and 30%, respectively, p < 0.05). In addition, systemic features were more frequent in early-onset FSHD, most important, hearing loss, decreased respiratory function and spinal deformities. There was no difference in work status. Genetically, the shortest D4Z4 repeat arrays (2–3 units) were found exclusively in the early-onset group, and the largest repeat arrays (8–9 units) were found only in the classic-onset groups. De novo mutations were more frequent in early-onset patients (46% vs 4%).ConclusionsPatients with early-onset FSHD more often have severe muscle weakness and systemic features. The disease severity is greater than in patients with classic-onset FSHD who are matched for disease duration, suggesting that the progression is faster in early-onset patients.

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Identification of Variants in Primary and Recurrent Glioblastoma Using a Cancer-Specific Gene Panel and Whole Exome Sequencing

PLoS ONE ◽

10.1371/journal.pone.0124178 ◽

2015 ◽

Vol 10 (5) ◽

pp. e0124178 ◽

Cited By ~ 12

Author(s):

Selene M. Virk ◽

Richard M. Gibson ◽

Miguel E. Quinones-Mateu ◽

Jill S. Barnholtz-Sloan

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Recurrent Glioblastoma ◽

Gene Panel ◽

Specific Gene ◽

Whole Exome

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Genetic diagnosis of congenital hypopituitarism by a target gene panel: novel pathogenic variants in GLI2, OTX2 and GHRHR

Endocrine Connections ◽

10.1530/ec-19-0085 ◽

2019 ◽

Vol 8 (5) ◽

pp. 590-595 ◽

Cited By ~ 2

Author(s):

Marilena Nakaguma ◽

Fernanda A Correa ◽

Lucas S Santana ◽

Anna F F Benedetti ◽

Ricardo V Perez ◽

...

Keyword(s):

Target Gene ◽

Gh Deficiency ◽

Massively Parallel Sequencing ◽

Genetic Diagnosis ◽

Pituitary Hormones ◽

Gene Panel ◽

Massively Parallel ◽

Parallel Sequencing ◽

Pathogenic Variants ◽

Congenital Hypopituitarism

Aim Congenital hypopituitarism has an incidence of 1:3500–10,000 births and is defined by the impaired production of pituitary hormones. Early diagnosis has an impact on management and genetic counselling. The clinical and genetic heterogeneity of hypopituitarism poses difficulties to select the order of genes to analyse. The objective of our study is to screen hypopituitarism genes (candidate and previously related genes) simultaneously using a target gene panel in patients with congenital hypopituitarism. Methods Screening of 117 subjects with congenital hypopituitarism for pathogenic variants in 26 genes associated with congenital hypopituitarism by massively parallel sequencing using a customized target gene panel. Results We found three novel pathogenic variants in OTX2 c.295C>T:p.Gln99*, GLI2 c.1681G>T:p.Glu561* and GHRHR c.820_821insC:p.Asp274Alafs*113, and the previously reported variants in GHRHR c.57+1G>A and PROP1 [c.301_302delAG];[c.109+1G>A]. Conclusions Our results indicate that a custom-designed panel is an efficient method to screen simultaneously variants of biological and clinical relevance for congenital GH deficiency. A genetic diagnosis was possible in 5 out of 117 (4%) patients of our cohort. We identified three novel pathogenic variants in GHRHR, OTX2 and GLI2 expanding the spectrum of variants associated with congenital hypopituitarism.

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Evaluation of nasal mucociliary clearance in rheumatoid arthritis: a comparative analysis using saccharin test

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20174964 ◽

2017 ◽

Vol 5 (11) ◽

pp. 5026 ◽

Cited By ~ 1

Author(s):

Shelja Deswal ◽

Jyoti Yadav ◽

Mohit Deswal ◽

Harpreet Singh

Keyword(s):

Rheumatoid Arthritis ◽

Disease Duration ◽

Mucociliary Clearance ◽

Systemic Disease ◽

Unknown Etiology ◽

Control Group ◽

Ciliary Activity ◽

Multisystem Disease ◽

Organic Particles ◽

Nasal Mucociliary Clearance

Background: Rheumatoid arthritis (RA) is a chronic multisystem disease of unknown etiology characterized by persistent inflammatory synovitis, usually involving peripheral joints in a symmetric distribution. RA is a systemic disease often associated with cutaneous and organ-specific extra-articular manifestations the mucociliary clearance system protects the lower respiratory system by trapping and removing inhaled pathogenic viruses and bacteria, in addition to nontoxic and toxic particulates (e.g., pollen, ash, mineral dust, mold spores, and organic particles), from the lungs. Effective clearance requires both ciliary activity and the appropriate balance of periciliary fluid and mucus.Methods: This was a case control study conducted in the Department of Physiology, Pt. B.D. Sharma PGIMS, Rohtak in 50 females of age group 30-50 years. Control group comprised of 25 healthy volunteer females while study group comprised of 25 rheumatoid arthritis female patients with disease duration of more than five years. Proven cases of RA (as per 1987 ACR criteria) were taken with disease duration of more than five years from Rheumatology clinic of Pt. B.D. Sharma PGIMS, Rohtak. Nasal mucociliary clearance time was evaluated by saccharin method.Results: The results of our study showed abnormal mucociliary clearance in rheumatoid arthritis patients.Conclusions: The study shows an abnormal mucociliary clearance in rheumatoid arthritis patients. Impairment of mucociliary clearance seems to be the result of qualitative and quantitative alterations in respiratory secretions.

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