Statistical guidance for experimental design and data analysis of mutation detection in rare monogenic mendelian diseases by exome sequencing.

PloS One
Degui Zhi, Rui Chen

Abstract

Recently, whole-genome sequencing, especially exome sequencing, has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. However, it is unclear whether this approach can be generalized and effectively applied to other Mendelian diseases with high locus heterogeneity. Moreover, the current exome sequencing approach has limitations such as false positive and false negative rates of mutation detection due to sequencing errors and other artifacts, but the impact of these limitations on experimental design has not been systematically analyzed. To address these questions, we present a statistical modeling framework to calculate the power, the probability of identifying truly disease-causing genes, under various inheritance models and experimental conditions, providing guidance for both proper experimental design and data analysis. Based on our model, we found that the exome sequencing approach is well-powered for mutation detection in recessive, but not dominant, Mendelian diseases with high locus heterogeneity. A disease gene responsible for as low as 5% of the disease population can be readily identified by sequencing just 200 unrelated patients. Based on these results, for identifying r...Continue Reading

Associated Clinical Trials

Mar 20, 2017·Stefano Gambardella

References

Feb 14, 2009·PLoS Genetics·Bo Eskerod Madsen, Sharon R Browning
Oct 8, 2009·Genetic Epidemiology·Andrew P Morris, Eleftheria Zeggini
Nov 17, 2009·Nature Genetics·Sarah B NgMichael J Bamshad
Jan 30, 2010·Journal of Child Neurology·Zulfikar ArlierMurat Gunel
Mar 12, 2010·The New England Journal of Medicine·James R LupskiRichard A Gibbs
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
Apr 1, 2010·Nature Methods·Gregory M CooperDeborah A Nickerson
Aug 3, 2010·Nature Methods·Jana Marie SchwarzDominik Seelow
Aug 17, 2010·Nature Genetics·Sarah B NgJay Shendure
Aug 20, 2010·Human Molecular Genetics·Jonathan RiosJonathan C Cohen
Sep 30, 2010·The Journal of Experimental Medicine·Minji ByunJean-Laurent Casanova
Oct 14, 2010·Nature Reviews. Genetics·Vikas BansalNicholas J Schork
Oct 29, 2010·Nature·Gonçalo R AbecasisGil A McVean
Nov 5, 2010·Annual Review of Genetics·Jennifer Asimit, Eleftheria Zeggini
Nov 26, 2010·Brain : a Journal of Neurology·Jun Ling WangBei Sha Tang
Dec 7, 2010·American Journal of Human Genetics·Dajiang J Liu, Suzanne M Leal

❮ Previous
Next ❯

Citations

Apr 18, 2014·Nature Reviews. Genetics·Pak C Sham, Shaun M Purcell
Feb 13, 2016·BMC Genetics·Stephanie A Santorico, Audrey E Hendricks
Feb 9, 2013·Science China. Life Sciences·Jacques ZaneveldRui Chen
Jul 16, 2015·Human Mutation·Michael GonzalezStephan Zuchner
Aug 5, 2015·Human Mutation·Peter KrawitzPeter N Robinson
Jun 14, 2013·Computational and Mathematical Methods in Medicine·Jo Nishino, Shuhei Mano
Aug 29, 2016·BMC Medical Genomics·Chen DuDavid R Adams
Feb 7, 2015·Journal of the American Medical Informatics Association : JAMIA·Shabbir Syed-AbdulYu-Chuan Li
Jul 19, 2013·Circulation. Cardiovascular Genetics·Quinn S WellsCharles C Hong
Jan 11, 2020·Journal of the American Society of Nephrology : JASN·Adam P LevineDaniel P Gale
Dec 19, 2018·Circulation. Genomic and Precision Medicine·Hisato SuzukiKenjiro Kosaki
Oct 12, 2018·Obesity Reviews : an Official Journal of the International Association for the Study of Obesity·A QasimD Meyre

❮ Previous
Next ❯

Methods Mentioned

BETA
exome sequencing
exome capture sequencing
exome-sequencing
exome capture

Software Mentioned

PolyPhen2
universally
SIFT
Td
MutationTaster
PolyPhen
Tr

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Brain : a Journal of Neurology
A B Singleton, J Raphael Gibbs
Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
Salman Kirmani
© 2022 Meta ULC. All rights reserved