Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort

Neurology
Sarah CummingOPTIMISTIC Consortium

Abstract

To evaluate the role of genetic variation at the DMPK locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life-Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial. We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats. We confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7-20.7, 2-tailed t test t = -3.7, p = 0.0019). Careful characterization of the DMPK CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route f...Continue Reading

References

Nov 21, 1991·Nature·A J JeffreysD G Monckton
Jun 1, 1989·Brain : a Journal of Neurology·C J HöwelerA Staal
Dec 1, 1993·Neurology·T AshizawaY Harati
Apr 21, 1993·JAMA : the Journal of the American Medical Association·J B RedmanC T Caskey
Dec 1, 1996·Journal of Medical Genetics·J P WarnerD J Brock
Mar 31, 2007·Genetic Testing·Leila Baghernajad SalehiGiuseppe Novelli
Jun 11, 2009·American Journal of Medical Genetics. Part a·Zuzana MusovaZdenek Sedlacek
Jul 24, 2014·European Journal of Human Genetics : EJHG·Fernando MoralesDarren G Monckton
Apr 6, 2016·Orphanet Journal of Rare Diseases·Sigrid BaldanziGabriele Siciliano
Nov 24, 2016·European Journal of Human Genetics : EJHG·Annalisa BottaGiuseppe Novelli

❮ Previous
Next ❯

Citations

Jan 16, 2020·International Journal of Molecular Sciences·Stéphanie Tomé, Geneviève Gourdon
Jan 1, 2020·Acta Neurologica Scandinavica·Erik LandfeldtHanns Lochmüller
Jul 11, 2020·Genes·Alfonsina Ballester-LopezGisela Nogales-Gadea
Aug 28, 2020·Neurology. Genetics·Jacob N MillerPeggy C Nopoulos
Nov 3, 2020·Disability and Rehabilitation·Kateri RaymondCynthia Gagnon
Dec 8, 2020·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·Matteo GaribaldiGiovanni Antonini
Jan 21, 2021·Cell Reports·Brittney A OteroEric T Wang
Feb 7, 2021·Neuromuscular Disorders : NMD·Sarah A CummingMaria Elena Farrugia
Oct 30, 2020·Frontiers in Neurology·Costanza SimonciniGabriele Siciliano
Feb 25, 2021·Molecular Genetics & Genomic Medicine·Russell J ButterfieldRobert B Weiss
Apr 4, 2021·International Journal of Molecular Sciences·Antoine ManginStéphanie Tomé
Apr 23, 2021·Neurology. Genetics·Stephan WenningerBenedikt Schoser
Jul 16, 2021·Frontiers in Neuroscience·Stefan HintzePeter Meinke
Jul 13, 2021·Journal of Neuromuscular Diseases·Daniël van AsUNKNOWN OPTIMISTIC consortium
Nov 28, 2021·International Journal of Molecular Sciences·Virginia Veronica ViscontiAnnalisa Botta

❮ Previous
Next ❯

Methods Mentioned

BETA
PCR
electrophoresis
PCRs

Clinical Trials Mentioned

NCT02118779

Software Mentioned

CLIQS
RStudio
R
R Stats
OPTIMISTIC

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

Annals of Noninvasive Electrocardiology : the Official Journal of the International Society for Holter and Noninvasive Electrocardiology, Inc
Bradley A HardinWilliam J Groh
Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia
Daisuke FurutamaToshiaki Hanafusa
© 2021 Meta ULC. All rights reserved