PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: Summary of the literature and implications for genetic testing

Andrew P. Landstrom, Babatunde A. Adekola, J. Martijn Bos, Steve R. Ommen, Michael John Ackerman

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is a major cause of sudden death in young athletes and one of the most common inherited cardiovascular diseases, affecting 1 in 500 individuals. Often viewed as a disease of the cardiac sarcomere, mutations in genes encoding myofilament proteins are associated with disease pathogenesis. Despite a clinically available genetic test, a significant portion of HCM patients remain genetically unexplained. We sought to determine the spectrum and prevalence of mutations in PLN-encoded phospholamban in a large cohort of HCM cases as a potential cause of mutation-negative HCM. Methods: Comprehensive genetic interrogation of the promoter and coding region of PLN was conducted using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing. Results: One L39X nonsense mutation was identified in 1 of 1,064 HCM proband cases with a family history of HCM, previously found to be negative for the current HCM genetic test panel. This mutation cosegregated with incidence of HCM in a multigenerational family. Compared with similar studies, we identified an overall yield of PLN-HCM mutations of 0.65%, similar to 3 genes that are part of current HCM genetic test panels. We did not observe any PLN coding sequence genetic variation in 600 reference alleles. Conclusions: Overall, mutations in PLN are rare in frequency, yet the small size of the genetic locus may make it amenable to inclusion on HCM gene test panels, especially because the frequency of background genetic variation among otherwise healthy subjects appears negligible. The exact role of mutations in PLN and other calcium-handling proteins in the development of HCM warrants further investigation.

Original languageEnglish (US)
Pages (from-to)165-171
Number of pages7
JournalAmerican Heart Journal
Volume161
Issue number1
DOIs
StatePublished - Jan 2011

Fingerprint

Hypertrophic Cardiomyopathy
Genetic Testing
Mutation
Genetic Promoter Regions
phospholamban
Genes
Sarcomeres
Genetic Loci
Myofibrils
Nonsense Codon
Sudden Death
DNA Sequence Analysis
Athletes
Cause of Death
Heart Diseases
Healthy Volunteers
Proteins
Cardiovascular Diseases
Alleles
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases : Summary of the literature and implications for genetic testing. / Landstrom, Andrew P.; Adekola, Babatunde A.; Bos, J. Martijn; Ommen, Steve R.; Ackerman, Michael John.

In: American Heart Journal, Vol. 161, No. 1, 01.2011, p. 165-171.

Research output: Contribution to journalArticle

@article{2de4dbb5788f49c095677b9d77dbcf88,
title = "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: Summary of the literature and implications for genetic testing",
abstract = "Background: Hypertrophic cardiomyopathy (HCM) is a major cause of sudden death in young athletes and one of the most common inherited cardiovascular diseases, affecting 1 in 500 individuals. Often viewed as a disease of the cardiac sarcomere, mutations in genes encoding myofilament proteins are associated with disease pathogenesis. Despite a clinically available genetic test, a significant portion of HCM patients remain genetically unexplained. We sought to determine the spectrum and prevalence of mutations in PLN-encoded phospholamban in a large cohort of HCM cases as a potential cause of mutation-negative HCM. Methods: Comprehensive genetic interrogation of the promoter and coding region of PLN was conducted using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing. Results: One L39X nonsense mutation was identified in 1 of 1,064 HCM proband cases with a family history of HCM, previously found to be negative for the current HCM genetic test panel. This mutation cosegregated with incidence of HCM in a multigenerational family. Compared with similar studies, we identified an overall yield of PLN-HCM mutations of 0.65{\%}, similar to 3 genes that are part of current HCM genetic test panels. We did not observe any PLN coding sequence genetic variation in 600 reference alleles. Conclusions: Overall, mutations in PLN are rare in frequency, yet the small size of the genetic locus may make it amenable to inclusion on HCM gene test panels, especially because the frequency of background genetic variation among otherwise healthy subjects appears negligible. The exact role of mutations in PLN and other calcium-handling proteins in the development of HCM warrants further investigation.",
author = "Landstrom, {Andrew P.} and Adekola, {Babatunde A.} and Bos, {J. Martijn} and Ommen, {Steve R.} and Ackerman, {Michael John}",
year = "2011",
month = "1",
doi = "10.1016/j.ahj.2010.08.001",
language = "English (US)",
volume = "161",
pages = "165--171",
journal = "American Heart Journal",
issn = "0002-8703",
publisher = "Mosby Inc.",
number = "1",

}

TY - JOUR

T1 - PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases

T2 - Summary of the literature and implications for genetic testing

AU - Landstrom, Andrew P.

AU - Adekola, Babatunde A.

AU - Bos, J. Martijn

AU - Ommen, Steve R.

AU - Ackerman, Michael John

PY - 2011/1

Y1 - 2011/1

N2 - Background: Hypertrophic cardiomyopathy (HCM) is a major cause of sudden death in young athletes and one of the most common inherited cardiovascular diseases, affecting 1 in 500 individuals. Often viewed as a disease of the cardiac sarcomere, mutations in genes encoding myofilament proteins are associated with disease pathogenesis. Despite a clinically available genetic test, a significant portion of HCM patients remain genetically unexplained. We sought to determine the spectrum and prevalence of mutations in PLN-encoded phospholamban in a large cohort of HCM cases as a potential cause of mutation-negative HCM. Methods: Comprehensive genetic interrogation of the promoter and coding region of PLN was conducted using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing. Results: One L39X nonsense mutation was identified in 1 of 1,064 HCM proband cases with a family history of HCM, previously found to be negative for the current HCM genetic test panel. This mutation cosegregated with incidence of HCM in a multigenerational family. Compared with similar studies, we identified an overall yield of PLN-HCM mutations of 0.65%, similar to 3 genes that are part of current HCM genetic test panels. We did not observe any PLN coding sequence genetic variation in 600 reference alleles. Conclusions: Overall, mutations in PLN are rare in frequency, yet the small size of the genetic locus may make it amenable to inclusion on HCM gene test panels, especially because the frequency of background genetic variation among otherwise healthy subjects appears negligible. The exact role of mutations in PLN and other calcium-handling proteins in the development of HCM warrants further investigation.

AB - Background: Hypertrophic cardiomyopathy (HCM) is a major cause of sudden death in young athletes and one of the most common inherited cardiovascular diseases, affecting 1 in 500 individuals. Often viewed as a disease of the cardiac sarcomere, mutations in genes encoding myofilament proteins are associated with disease pathogenesis. Despite a clinically available genetic test, a significant portion of HCM patients remain genetically unexplained. We sought to determine the spectrum and prevalence of mutations in PLN-encoded phospholamban in a large cohort of HCM cases as a potential cause of mutation-negative HCM. Methods: Comprehensive genetic interrogation of the promoter and coding region of PLN was conducted using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing. Results: One L39X nonsense mutation was identified in 1 of 1,064 HCM proband cases with a family history of HCM, previously found to be negative for the current HCM genetic test panel. This mutation cosegregated with incidence of HCM in a multigenerational family. Compared with similar studies, we identified an overall yield of PLN-HCM mutations of 0.65%, similar to 3 genes that are part of current HCM genetic test panels. We did not observe any PLN coding sequence genetic variation in 600 reference alleles. Conclusions: Overall, mutations in PLN are rare in frequency, yet the small size of the genetic locus may make it amenable to inclusion on HCM gene test panels, especially because the frequency of background genetic variation among otherwise healthy subjects appears negligible. The exact role of mutations in PLN and other calcium-handling proteins in the development of HCM warrants further investigation.

UR - http://www.scopus.com/inward/record.url?scp=78650272451&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650272451&partnerID=8YFLogxK

U2 - 10.1016/j.ahj.2010.08.001

DO - 10.1016/j.ahj.2010.08.001

M3 - Article

C2 - 21167350

AN - SCOPUS:78650272451

VL - 161

SP - 165

EP - 171

JO - American Heart Journal

JF - American Heart Journal

SN - 0002-8703

IS - 1

ER -