PLN in Hypertrophic Cardiomyopathy (HCM)

Evidence for role of PLN in HCM

A detailed analysis of the role of non-sarcomeric genes in HCM - incorporating clinical sequencing data from the OMGL and LMM labs, a cohort of over 800 HCM probands from the Royal Brompton Hospital, London and the National Heart Centre, Singapore (sequenced on a broad cardiac NGS panel) and published sequencing, segregation and functional data - has clarified the involvement of PLN variants in this condition (see our study published in the European Heart Journal for further details).

Based on this analysis, PLN is classified as having: Strong Evidence

Case excess (gene)Max LOD scoreCase excess (variant)De novo variant
p<0.0001- -
See details below p.L39X (4/5435 cases vs. 1/60671 ExAC samples, p=2x10-4)

Cohort (reference)HCM patients testedRare variantsCase FrequencySignificance vs ExAC
12705874 87 0 0.00000 no excess
16382369 53 0 0.00000 no excess
16829191 101 0 0.00000 no excess
17655857 252 1 0.00397 p=0.117
18409188 38 0 0.00000 no excess
21167350 1064 1 0.00094 p=0.408
25351510 874 7 0.00801 p<0.0001
27532257 2167 7 0.00323 p=0.0002
28082330 804 2 0.00249 p=0.062
Total 5440 18 0.00331 p<0.0001

Summary of the frequency of rare PLN variants (ExAC frequency < 0.0001) in published cohorts of HCM probands. P-values shown are from Fisher' Exact test compared to rare variants in ExAC (ExAC frequency = 0.00048). Significance is based on multiple testing correction of 31 genes tested (p<0.0016).

Data from clinical cohorts

By comparing the frequency of PLN variants in large HCM clinical cohorts to the background population rate in the ExAC database, the proportion of HCM patients with pathogenic mutations in PLN can be estimated, as well as the likelihood that a rare (population allele frequency <0.0001) PLN variant identified in a HCM patient is disease-causing. Summary data for different variant classes (all protein-altering variants, loss of function truncating variants and non-truncating variants) is highlighted - see the table below for full details of this analysis.

Excess of PLN variants in HCM: 0.28% (p=0.0002)

Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in PLN found in 2167 HCM samples sequenced by OMGL and LMM and in reference samples of the ExAC population database.

Metrics by Variant Class:
All VarsTruncatingNon-Truncating
Excess in HCM 0.28%
Etiological fraction 0.85
0.60 - 0.94
0.81 - 0.99
0.00 - 0.91
Odds Ratio 6.75
2.49 - 15.78
5.20 - 150.17
0.65 - 11.00

The Etiological Fraction (EF) is the proportion of affected carriers where the variant caused HCM. The Odds Ratio (OR) describes the odds of having a rare variant in the patient cohort to the odds in the ExAC cohort. Fisher's exact test p-values are displayed for case excess, 95% confidence intervals for EFs and ORs.

in HCM
in ExAC
Case Excess
in HCM
(OMGL1 + LMM2)
2167All7 0.003230.000480.00275
Truncating4 0.001850.000060.00179
Non-Truncating3 0.001380.000420.00096
OMGL11535All5 0.003260.000480.00278
Truncating3 0.001950.000060.00189
Non-Truncating2 0.001300.000420.00088
LMM2632All2 0.003160.000480.00268
Truncating1 0.001580.000060.00152
Non-Truncating1 0.001580.000420.00116


1. Roddy Walsh, Kate L. Thomson, James S. Ware, Birgit H. Funke, Jessica Woodley, Karen J. McGuire, Francesco Mazzarotto, Edward Blair, Anneke Seller, Jenny C. Taylor, Eric V. Minikel, Exome Aggregation Consortium, Daniel G. MacArthur, Martin Farrall, Stuart A. Cook and Hugh Watkins. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 doi:10.1038/gim.2016.90.

2. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8.

3. Roddy Walsh, Rachel Buchan, Alicja Wilk, Shibu John, Leanne E. Felkin, Kate L. Thomson, Tang Hak Chiaw, Calvin Chin Woon Loong, Chee Jian Pua, Claire Raphael, Sanjay Prasad, Paul J. Barton, Birgit Funke, Hugh Watkins, James S. Ware, Stuart A. Cook. Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes. Eur Heart J. 2017 doi:10.1093/eurheartj/ehw603.