The long tail and rare disease research: the impact of next-generation sequencing for rare Mendelian disorders

Shen, Tony S.; Lee, Ariel; Shen, Carol; Lin, Cheng-Ho Jimmy

doi:10.1017/s0016672315000166

Cited by 22 publications

(19 citation statements)

References 89 publications

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“…We used a human phenotype ontology (HPO) term (Shen et al, ) to classify the primary disease of the patient that can be annotated by his clinical notes, which is essential for variant interpretation in our cohort characteristic of clinically and genetically heterogeneous disorders.…”

Section: Methodsmentioning

confidence: 99%

“…Although traditional gene mapping approaches, such as Sanger sequencing (Botstein & Risch, ), linkage analysis (Teare & Santibanez Koref, ), and homozygosity mapping (Lander & Botstein, ) have led to great insights into Mendelian diseases over the past few decades; they are unable to detect all forms of variation in a single experiment. The rapid development of next generation sequencing (NGS) constituted a turning point for the advancement of our understanding of this type of diseases, which requires a broad search for causal variants across their genetically heterogeneous spectrum within a short time (Shen, Lee, Shen, & Lin, ), especially for life‐threatening or chronically debilitating cases. Today, different NGS techniques can be used for diagnostic purposes.…”

Section: Introductionmentioning

confidence: 99%

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Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

Hong

Wang

Zhao

et al. 2019

Molec Gen & Gen Med

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Background Rare diseases are complex disorders with huge variability in clinical manifestations. Decreasing cost of next‐generation sequencing (NGS) tests in recent years made it affordable. We witnessed the diagnostic yield and clinical use of different NGS strategies on a myriad of monogenic disorders in a pediatric setting. Methods Next‐generation sequencing tests are performed for 98 unrelated Chinese patients within their first year of life, who were admitted to Xin Hua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, during a 2‐year period. Results Clinical indications for NGS tests included a range of medical concerns. The mean age was 4.4 ± 4.2 months of age for infants undergoing targeting specific (known) disease‐causing genes (TRS) analysis, and 4.4 ± 4.3 months of age for whole‐exome sequencing (WES) (p > 0.05). A molecular diagnosis is done in 72 infants (73.47%), which finds a relatively high yield with phenotypes of metabolism/homeostasis abnormality (HP: 0001939) (odds ratio, 1.83; 95% CI, 0.56–6.04; p = 0.32) and a significantly low yield with atypical symptoms (without a definite HPO term) (odds ratio, 0.08; 95% CI, 0.01–0.73; p = 0.03). TRS analysis provides molecular yields higher than WES (p = 0.01). Ninety‐eight different mutations are discovered in 72 patients. Twenty‐seven of them have not been reported previously. Nearly half (43.06%, 31/72) of the patients are found to carry 11 common disorders, mostly being inborn errors of metabolism (IEM) and neurogenetic disorders and all of them are observed through TRS analysis. Eight positive cases are identified through WES, and all of them are sporadic, of highly variable phenotypes and severity. There are 26 patients with negative findings in this study. Conclusion This study provides evidence that NGS can yield high success rates in a tertiary pediatric setting, but suggests that the scope of known Mendelian conditions may be considerably broader than currently recognized.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

Hong

Wang

Zhao

et al. 2019

Molec Gen & Gen Med

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“…For ‘ultrarare’ diseases, in which candidate variants have only been identified in a handful of individuals within a single pedigree, validation of pathogenicity can be challenging. Additionally, because translational research efforts have historically been more focused on common disorders,7 the underlying mechanisms contributing to rare diseases often remain poorly understood, even where the genetic aetiology has been confirmed.…”

Section: The Importance Of Researching Rare Genetic Diseasesmentioning

confidence: 99%

Use of zebrafish models to investigate rare human disease

2018

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Rare diseases are collectively common and often extremely debilitating. Following the emergence of next-generation sequencing (NGS) technologies, the variants underpinning rare genetic disorders are being unearthed at an accelerating rate. However, many rare conditions lack effective treatments due to their poorly understood pathophysiology. There is therefore a growing demand for the development of novel experimental models of rare genetic diseases, so that potentially causative variants can be validated, pathogenic mechanisms can be investigated and therapeutic targets can be identified. Animal models of rare diseases need to be genetically and physiologically similar to humans, and well-suited to large-scale experimental manipulation, considering the vast number of novel variants that are being identified through NGS. The zebrafish has emerged as a popular model system for investigating these variants, combining conserved vertebrate characteristics with a capacity for large-scale phenotypic and therapeutic screening. In this review, we aim to highlight the unique advantages of the zebrafish over other in vivo model systems for the large-scale study of rare genetic variants. We will also consider the generation of zebrafish disease models from a practical standpoint, by discussing how genome editing technologies, particularly the recently developed clustered regularly interspaced repeat (CRISPR)/CRISPR-associated protein 9 system, can be used to model rare pathogenic variants in zebrafish. Finally, we will review examples in the literature where zebrafish models have played a pivotal role in confirming variant causality and revealing the underlying mechanisms of rare diseases, often with wider implications for our understanding of human biology.

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“…In the last decade, next-generation sequencing (NGS) has emerged as an effective tool for detecting single nucleotide variants (SNVs) causing rare conditions [1]. Recent retrospective studies have demonstrated an increase of 25-31% in diagnostic yield of rare diseases due to the application of exome or whole genome sequencing in a clinical framework [2,3]. Through comparison against human genome reference sequence, high-quality NGS data on individual patients can be used to identify variation in variant call files (VCF).…”

Section: Introductionmentioning

confidence: 99%

GenePy – a score for estimating gene pathogenicity in individuals using next-generation sequencing data

Mossotto

Ashton

Pengelly

et al. 2018

Preprint

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The long tail and rare disease research: the impact of next-generation sequencing for rare Mendelian disorders

Cited by 22 publications

References 89 publications

Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

Use of zebrafish models to investigate rare human disease

GenePy – a score for estimating gene pathogenicity in individuals using next-generation sequencing data

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