Whole exome and targeted gene sequencing to detect pathogenic recessive variants in early onset cerebellar ataxia

Shakya, Sunil; Kumari, Renu; Suroliya, Varun; Tyagi, Nishu; Joshi, Aditi; Garg, Ajay; Singh, Inder; Puthanveedu, Divya Kalikavil; Cherian, Ajith; Mukerji, Mitali; Srivastava, Achal K.; Faruq, Mohammed

doi:10.1111/cge.13625

Cited by 20 publications

(14 citation statements)

References 14 publications

(23 reference statements)

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“…More information on the utility of NGS in early-onset cerebellar ataxias (EOCAs) comes from studies on larger series of adults, whose symptoms started appearing before the age of 40. Overall, they showed a diagnostic yield of NGS ranging from 21% to over 50%, with higher percentages of molecular diagnoses in patients with a positive family history compatible with Mendelian inheritance [20,[32][33][34][35][36][37][38][39]. The results of NGS studies outlined the most common etiologies of EOCAs in different populations.…”

Section: Utility Of Next-generation Sequencing In Childhood-onset Cerebellar Ataxiasmentioning

confidence: 95%

“…Studies show that AD has a significant polygenic component, which may be used in calculating genetic risk of developing the disease. The sum of risk alleles carried by an individual, where each single nucleotide polymorphism (SNP) is weighted by the effect [20,21,24,[32][33][34][35][36] size from the prior GWAS, is called a polygenic risk score (PRS) and may have a predictive value for multiple common diseases. Promising results that point to potential clinical utility of PRS in the future have been published for AD and epilepsy [63,64].…”

Section: Cerebellar Ataxias-beyond Monogenic Diseasesmentioning

confidence: 99%

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Milestones in genetics of cerebellar ataxias

Krygier

Mazurkiewicz-Bełdzińska

2021

Neurogenetics

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Cerebellar ataxias (CAs) comprise a group of rare, neurological disorders characterized by extensive phenotypic and genetic heterogeneity. The core clinical feature is the cerebellar syndrome, which is often accompanied by other neurological or non-neurological signs. In the last 30 years, our understanding of the CA etiology has increased significantly, and numerous ataxia-associated genes have been discovered. Conventional variants or tandem repeat expansions, localized in the coding or non-coding DNA sequences, lead to hereditary ataxia, which can display different patterns of inheritance. Advances in molecular techniques have enabled a rapid and cost-effective detection of causative variants in a significant number of CA patients. However, despite performing extensive investigations, a definite diagnosis is still unknown in the majority of affected individuals. In this review, we discuss the major advances in the genetics of CAs over the last 30 years, focusing on the impact of next-generation sequencing on the genetic landscape of childhood- and adult-onset CAs. Additionally, we outline possible directions for further genetic research in hereditary and sporadic CAs in the era of increasing application of whole-genome sequencing and genome-wide association studies in various neurological disorders.

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Section: Utility Of Next-generation Sequencing In Childhood-onset Cerebellar Ataxiasmentioning

confidence: 95%

Section: Cerebellar Ataxias-beyond Monogenic Diseasesmentioning

confidence: 99%

Milestones in genetics of cerebellar ataxias

Krygier

Mazurkiewicz-Bełdzińska

2021

Neurogenetics

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“…Besides, 11 ethnically matched controls' with an age range of 65-90 years were also included for WES (variant prioritization). DNA samples of 257 healthy individuals of age >40 years were used for frequency estimation of the prioritized variants in the background population and performed genotyping of variants using Sequenom iPLEX Gold Massarray platform 9 . For segregation analysis, we have used samples of informative family members of 15 families.…”

Section: Methodsmentioning

confidence: 99%

“…Whole exome sequencing (WES) as a high throughput tool for detection of all coding variants, has been found to be more e cient than other genetic tools at improving diagnostic yield and enabling novel gene discoveries [6][7][8] . Our previous study in autosomal recessive CA (ARCA) families has enabled us to identify both, already reported as well as novel variants in typical and atypical ataxia genes with a much higher diagnostic yield (56%) using WES, as compared to targeted resequencing 9,10 . WES could therefore be a more appropriate tool for genetic delineation in otherwise unresolved cases of CA families, speci cally the sporadic CA occurrences.…”

Section: Introductionmentioning

confidence: 99%

Integrated whole exome sequencing and functional approach delineate genetic heterogeneity in cerebellar ataxias

Kumari

Uppilli

Shakya

et al. 2021

Preprint

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PurposeDisease deconvolution in heterogeneous cerebellar ataxias (CAs) needs a focussed approach to overcome the diagnostic challenges. A diverse clinical presentation with over 100 reported genetic loci, in addition to the various challenges associated with genotype-phenotype correlation complicate the genetic diagnosis in 40-60% of the CA cases that remain uncharacterized. We present here an integrated whole exome sequencing combined with a functional validation approach to delineate the genetic etiology in Indian CA patients.MethodA total of 50 familial and sporadic progressive CA families (negative for CNG expansion) including 101 subjects were recruited for this study. Index patients from 50 families were subjected to singleton whole exome sequencing (S-WES). Family-based WES (F-WES) was carried out for seven S-WES selected families. Protein simulation and docking studies were performed for seven genetic variants identified through WES. A Cell line-based model was used to assess disease signatures for variants in KCNC3 and a new candidate gene, SPTB.ResultsClinically relevant variants identified in 70% (35/50) of the selected families. We achieved a 50% (25/50) definitive diagnostic yield and 14% (7/50) probable diagnostic yield while 6% (3/50) of the families showed variants of uncertain significance. We prioritized compound heterozygous variants in a candidate gene, SPTB for cerebellar ataxia with hereditary spherocytosis. Lymphoblastoid cell line derived from a patient with a KCNC3 variant showed altered disease signatures with induced ROS and elevated unfolded protein response markers at the basal level.ConclusionOur results highlight an extensive experimental design for the genetic diagnosis of CA. Through targeted analysis of ataxia phenotype-derived gene panel in S-WES, new gene identification through F-WES, and revaluation of unsolved families’ WES data, we identified novel, reported and other clinically relevant variants in CA patients. Bioinformatic protein modeling along with the cellular insights into the pathogenicity of novel variants enabled delineation of genetic diagnostics and enhanced the mechanistic understanding of CAs.

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“…The yield of genetic testing in adult neurology has been mostly evaluated in research settings and for specific diagnostic categories with restricted inclusion criteria (Fernández et al, 2019; Gorcenco et al, 2020; Haskell et al, 2018; Shakya et al, 2019; Winder et al, 2020). However, in clinical practice, genetic testing is increasingly obtained via commercial laboratories for a broad spectrum of neurology patients (Fogel et al, 2016; Guerreiro et al, 2014; Krenn et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Temporal trends and yield of clinical diagnostic genetic testing in adult neurology

Guo

Bardakjian

Brzozowski

et al. 2021

American J of Med Genetics Pt A

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While genetics evaluation is increasingly utilized in adult neurology patients, its usage and efficacy are not well characterized. Here, we report our experience with 1461 consecutive patients evaluated in an adult neurogenetics clinic at a large academic medical center between January 2015 and March 2020. Of the 1461 patients evaluated, 1215 patients were referred for the purposes of identifying a genetic diagnosis for an undiagnosed condition, 90.5% of whom underwent genetic testing. The modalities of genetic testing utilized varied across referral diagnostic categories, including a range of utilization of whole exome sequencing (WES) as an initial test in 13.9% of neuromuscular patients to 52.9% in white matter disorder patients. The usage of WES increased over time, from 7.7% of initial testing in 2015 to a peak of 27.3% in 2019. Overall, genetic testing yielded a causal genetic diagnosis in 30.7% of patients. This yield was higher in certain referring diagnosis categories, such as neuromuscular (39.0%) and epilepsy (29.8%). Our study demonstrates that evaluation at an adult neurogenetics referral center can yield diagnoses in a substantial fraction of patients. Additional research will be needed to determine optimal genetic testing strategies and cost effectiveness of adult neurogenetics evaluation.

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Whole exome and targeted gene sequencing to detect pathogenic recessive variants in early onset cerebellar ataxia

Cited by 20 publications

References 14 publications

Milestones in genetics of cerebellar ataxias

Milestones in genetics of cerebellar ataxias

Integrated whole exome sequencing and functional approach delineate genetic heterogeneity in cerebellar ataxias

Temporal trends and yield of clinical diagnostic genetic testing in adult neurology

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