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Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers

Nishiuchi, Suguru 京都大学 DOI:10.14989/doctor.r13568

2023.09.25

概要

Gene-Based Risk Stratification for
Cardiac Disorders in LMNA Mutation
Carriers
（ラミン遺伝子変異キャリアにおける遺伝子
型を用いた心疾患リスクの層別化）

西内

英

主論文

Original Article
Gene-Based Risk Stratification for Cardiac Disorders
in LMNA Mutation Carriers
Suguru Nishiuchi, MD; Takeru Makiyama, MD, PhD; Takeshi Aiba, MD, PhD;
Kenzaburo Nakajima, MD; Sayako Hirose, MD; Hirohiko Kohjitani, MD;
Yuta Yamamoto, DVM, PhD; Takeshi Harita, MD; Mamoru Hayano, MD; Yimin Wuriyanghai, MD;
Jiarong Chen, PhD; Kenichi Sasaki, MD, PhD; Nobue Yagihara, MD, PhD;
Taisuke Ishikawa, DVM, PhD; Kenji Onoue, MD, PhD; Nobuyuki Murakoshi, MD, PhD;
Ichiro Watanabe, MD, PhD; Kimie Ohkubo, MD, PhD; Hiroshi Watanabe, MD, PhD;
Seiko Ohno, MD, PhD; Takahiro Doi, MD, PhD; Satoshi Shizuta, MD, PhD;
Tohru Minamino, MD, PhD; Yoshihiko Saito, MD, PhD; Yasushi Oginosawa, MD, PhD;
Akihiko Nogami, MD, PhD; Kazutaka Aonuma, MD, PhD; Kengo Kusano, MD, PhD;
Naomasa Makita, MD, PhD; Wataru Shimizu, MD, PhD; Minoru Horie, MD, PhD;
Takeshi Kimura, MD, PhD

Downloaded from http://ahajournals.org by on December 7, 2019

Background—Mutations in LMNA (lamin A/C), which encodes lamin A and C, typically cause age-dependent cardiac
phenotypes, including dilated cardiomyopathy, cardiac conduction disturbance, atrial fibrillation, and malignant
ventricular arrhythmias. Although the type of LMNA mutations have been reported to be associated with susceptibility
to malignant ventricular arrhythmias, the gene-based risk stratification for cardiac complications remains unexplored.
Methods and Results—The multicenter cohort included 77 LMNA mutation carriers from 45 families; cardiac disorders
were retrospectively analyzed. The mean age of patients when they underwent genetic testing was 45±17, and they were
followed for a median 49 months. Of the 77 carriers, 71 (92%) were phenotypically affected and showed cardiac conduction
disturbance (81%), low left ventricular ejection fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular
arrhythmias (26%). During the follow-up period, 9 (12%) died, either from end-stage heart failure (n=7) or suddenly (n=2).
Genetic analysis showed truncation mutations in 58 patients from 31 families and missense mutations in 19 patients from
14 families. The onset of cardiac disorders indicated that subjects with truncation mutations had an earlier occurrence of
cardiac conduction disturbance and low left ventricular ejection fraction, than those with missense mutations. In addition, the
truncation mutation was found to be a risk factor for the early onset of cardiac conduction disturbance and the occurrence
of atrial arrhythmias and low left ventricular ejection fraction, as estimated using multivariable analyses.
Conclusions—The truncation mutations were associated with manifestation of cardiac phenotypes in LMNA-related
cardiomyopathy, suggesting that genetic analysis might be useful for diagnosis and risk stratification. (Circ Cardiovasc
Genet. 2017;10:e001603. DOI: 10.1161/CIRCGENETICS.116.001603.)
Key Words: arrhythmia ◼ cardiomyopathies ◼ death, sudden, cardiac ◼ heart failure ◼ lamin type A
◼ mutation ◼ prognosis

T

he LMNA (lamin A/C) gene encodes the A-type lamin
proteins, lamin A and C—the major components of the
nuclear membrane in vertebrates—and mutations in LMNA
have been reported to cause a variety of clinical phenotypes,
including cardiac disorders,1 Emery–Dreifuss muscular dystrophy,2,3 limb-girdle muscular dystrophy,4 Charcot–Marie–
Tooth type 2,5 familial partial lipodystrophy,6,7 and premature
aging.8,9 The cardiac phenotypes associated with LMNA mutations are characterized by cardiac conduction disturbance
(CCD), atrial fibrillation, ventricular tachyarrhythmia (VT),
and dilated cardiomyopathy.10–14

See Editorial by Sinagra et al
See Clinical Perspective
Risk stratification for LMNA-related cardiomyopathy has
been assessed previously in some reports. Approximately
90% of LMNA mutation carriers >30 years of age have some
type of arrhythmia, and the subjects have a risk of sudden
arrhythmic death before the development of cardiac failure15
Recently, Kumar et al16 reported the long-term follow-up data
of 122 consecutive LMNA mutation carriers and showed that
LMNA-related heart diseases had a malignant course; most

Received September 6, 2016; accepted September 25, 2017.
The Data Supplement is available at http://circgenetics.ahajournals.org/lookup/suppl/doi:10.1161/CIRCGENETICS.116.001603/-/DC1.
Correspondence to Takeru Makiyama, MD, PhD, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54
Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606–8507, Japan, E-mail makiyama@kuhp.kyoto-u.ac.jp or Takeshi Aiba, MD, PhD, Division of Arrhythmia
and Electrophysiology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565–8565 Japan, E-mail aiba@hsp.ncvc.go.jp
© 2017 American Heart Association, Inc.
Circ Cardiovasc Genet is available at http://circgenetics.ahajournals.org

1

DOI: 10.1161/CIRCGENETICS.116.001603

2 Nishiuchi et al Gene-Based Risk Stratification for Laminopathy
patients experienced arrhythmia, heart block, embolic events,
or heart failure within 7 years of diagnosis.
Several studies have also explored genotype–phenotype
correlations; frameshift mutations were often associated with
the cardiac disorders in laminopathies,17 and splice-site mutations were one of the independent risk factors for sudden
cardiac death.13 Recently, van Rijsingen et al18 revealed that
nonmissense mutations were (ins-del/truncating or mutations
affecting splicing) one of the major independent risk factors for
malignant ventricular arrhythmias (MVAs) in a large European
cohort of 269 LMNA mutation carriers. These results indicated
that patients with truncation LMNA mutations, which result in
haploinsufficiency of A-type lamins, might be at significantly
higher risk of sudden cardiac death because of MVAs, than
missense mutation carriers. However, other cardiac complications, such as left ventricular systolic dysfunction and CCD, in
LMNA mutation carriers have not yet been fully investigated in
terms of the type of mutations. Based on the available literature, we hypothesized that truncation mutations might be associated with poor prognosis in LMNA mutation carriers because
of CCD, MVAs, and heart failure. To test this hypothesis, we
performed a multicenter retrospective cohort study.

Methods
Study Design

Downloaded from http://ahajournals.org by on December 7, 2019

The cohort for the present study consisted of genotyped LMNA mutation carriers and their relatives who had been introduced to the Kyoto
University Hospital (Kyoto, Japan), Shiga University of Medical
Science (Shiga, Japan), Nagasaki University Graduate School of
Biomedical Sciences (Nagasaki, Japan), Niigata University Graduate
School of Medical and Dental Sciences (Niigata, Japan), University of
Tsukuba (Ibaraki, Japan), and the National Cerebral and Cardiovascular
Center (Osaka, Japan) for genetic screening of LMNA between April
2008 and October 2015. Carriers of compound heterozygous mutations
in LMNA and SCN5A were not included in this cohort. All subjects
willingly provided informed consent for participating in this study.
After providing informed consent, the patients were subjected to clinical screening and underwent peripheral blood sampling for genetic
testing. Detailed clinical information was obtained from each subject
by cardiologists in the respective institutes. After the genetic diagnosis, LMNA mutation carriers were followed up by a cardiologist from
one of the participating institutes or by a private doctor. The primary
end point in this analysis was all-cause death during the follow-up period. The secondary end point was a composite of cardiac events and
diagnosis, including the first occurrence of CCD, atrial arrhythmias,
low left ventricular ejection fraction (LVEF), or MVAs. The protocol
of this study was approved by the Institutional Ethics Committee and
performed in accordance with its guidelines (Kyoto University, G194;
National Cerebral and Cardiovascular Center, M24-031-4).

Genetic Analysis
The methods followed for DNA extraction, for generating the PCR
primers, and for mutational screening are described in Appendix in
the Data Supplement and Table I in the Data Supplement. The mutations were divided into 2 groups: truncation (including splice site,
frameshift insertion, frameshift deletion, and nonsense mutations)
and missense mutations. We also classified the mutations based on the
site: mutations located upstream (nuclear localization signal [NLS]
class 1) of the spanning residues 416 to 423 and mutations located
downstream (NLS class 2; Figure 1).13,19 If a frameshift or nonsense
mutation was located upstream of the NLS residue, or a missense mutation disturbed the base sequence of the NLS residue, it was defined
as an NLS-disturbed mutation. All the other mutations that did not
disturb the NLS sequence were defined as NLS-conserved mutations.

Bioinformatic Analysis
Variants in LMNA were screened by genetic variant databases, a splicing site prediction tool, and in silico predictions (details in Appendix
in the Data Supplement). Additionally, we confirmed the pathogenicity of mutations by using cascade screening, after accommodating
relatives. Of the 84 carriers from 51 families genotyped by screening, 7 carriers from 6 families were excluded (Table 1; Table II in
the Data Supplement) because unreported LMNA variants without
enough clinical or genetic data of relatives were considered variants
of unknown significance.

Clinical Definitions
Low LVEF was defined as LVEF <50%. ...

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参考文献

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CLINICAL PERSPECTIVE

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Mutations in LMNA (lamin A/C) gene are associated with several cardiac phenotypes, including cardiac conduction disturbance, atrial or ventricular tachyarrhythmias, and dilated cardiomyopathy, resulting in heart failure or sudden cardiac death;

however, risk stratification for LMNA-related cardiomyopathy has been still controversial. This multicenter cohort study has

shown a high prevalence of these cardiac disorders and major cardiac events in the LMNA mutation carriers, and multivariable analyses revealed that the truncation mutation in LMNA gene was associated with a risk for earlier onset of cardiac

conduction disturbance and the occurrence of atrial arrhythmias and low left ventricular ejection fraction, suggesting more

intensive follow-up is necessary in patients carrying truncation mutations. On the contrary, even though a missense mutation, the LMNA mutation carriers have some risk for the cardiac disorders and significant cardiac mortality. Moreover, this

study included only for subjects with typical LMNA-related cardiomyopathy called laminopathy and their relatives but not

included forme fruste LMNA carriers. Therefore, this study does not entirely clarify the full view of how LMNA mutations

manifest. Regarding the indication for device-based therapy, we would recommend the subjects carrying LMNA truncation

mutations to receive implantable cardioverter defibrillators (or cardiac resynchronization therapy defibrillators) because

of their high incidence of ventricular tachyarrhythmias observed over 40 years old. However, this study was not designed

to determine the effect of implantable cardioverter defibrillator therapy on mortality or quality of daily activity, we cannot

completely define the efficacy of prophylactic implantable cardioverter defibrillator implantation in the early age. Further

prospective study may disclose appropriate indications for implantable cardioverter defibrillator (or cardiac resynchronization therapy defibrillator) implantation for LMNA mutation carriers.

主論文補足資料

SUPPLEMENTAL MATERIAL

Methods

Genetic analysis

Genomic deoxyribonucleic acid was extracted from peripheral blood leukocytes using a

DNA isolation kit for Mammalian Blood (Roche Diagnostics, Basel, Switzerland). Standard

polymerase chain reaction (PCR) primers were derived from intronic sequences (Table S1)

to amplify the 12 protein-coding exons of LMNA. Mutational screenings of PCR amplicons

were performed by direct sequencing on an ABI PRISM 3130x Genetic Analyzer (Thermo

Fisher Scientific, Waltham, Massachusetts) by using BigDye Terminator chemistry (v1.1 or

3.1) according to standard protocols. Reference sequences used in this study are as follows:

LMNA gene: NCBI NC_000001; LMNA messenger ribonucleic acid: NCBI NM_170707;

lamin A protein: NCBI NP_733821; LMNC messenger ribonucleic acid: NCBI NM_005572;

lamin C protein: NCBI NP_005563. Mutations were categorized in two ways based on type

and site.

Bioinformatic analysis

Mutations present in the dbSNP build 146 or published in the literature were identified. All

non-matching variants were filtered using a minor allele frequency threshold <0.3% based

on the Human Genetic Variation Database (http://www.genome.med.kyoto-u.ac.jp/SnpDB/),

which

included

the

Japanese

population,

Exome

Aggregation

Consortium

(http://exac.broadinstitute.org), and ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/). All

single base substitutions without changes in the coding amino acid were screened by a

splicing site prediction tool (Berkeley Drosophila Genome Project: http://www.fruitfly.org),

and the possibility of aberrant splicing was estimated. The candidate variant was considered

as a pathogenic mutation if it generated a stop codon, a frameshift of the open reading frame,

or an aberrant splice site. The pathogenicity of novel missense variants was screened by in

silico

predictions

using

Polyphen2

(http://genetics.bwh.harvard.edu/pph2/),

SIFT

(http://sift.jcvi.org/), and Condel (http://bg.upf.edu/fannsdb/). A novel missense variant was

considered pathogenic if classified as ‘probably damaging’ by Polyphen2, ‘damaging’ by

SIFT, or predicted to be ‘deleterious’ by Condel.

List of Participating Institutes and Investigators for this cohort study:

National Cerebral and Cardiovascular Center: Kenzaburo Nakajima, Koko Asakura, Takeshi

Aiba, Kengo Kusano

Kyoto University Graduate School of Medicine: Takeru Makiyama, Takahiro Doi, Satoshi

Shizuta, Takeshi Kimura

Shiga University of Medical Science: Tetshuhisa Hattori, Seiko Ohno, Minoru Horie

Nagasaki University Graduate School of Biomedical Science: Taisuke Ishikawa, Naomasa

Makita

University of Tsukuba: Nobuyuki Murakoshi, Akihiko Nogami, Kazutaka Aonuma

Nippon Medical School Hospital: Wataru Shimizu

Niigata University Graduate School of Medical and Dental Sciences: Nobue Yagihara,

Hiroshi Watanabe, Tohru Minamino

Yokohama Rosai Hospital: Nobuyuki Murakoshi, Akihiko Nogami

Nara Medical University Hospital: Kenji Onoue, Yoshihiko Saito

University of Occupational and Environmental Health Hospital: Yasushi Oginosawa

Nihon University Itabashi Hospital: Ichiro Watanabe, Kimie Ohkubo

Hokkaido University: Naomasa Makita

Tenri Hospital: Kazuhiro Kaitani, Yoshihisa Nakagawa

Oita University Hospital: Naohiko Takahashi

Chiba University Hospital: Motoi Nishimura

Kitano Hospital: Tetsuya Haruna, Kenichi Sasaki

Japanese Red Cross Hadano Hospital: Yusuke Matsumoto

Ijin-kai Takeda Hospital: Takeru Makiyama

Dokkyo Medical University Koshigaya Hospital: Naofumi Tsukada

Fujimoto-chuo Hospital: Koji Sakata

Iida Municipal Hospital: Yuichi Katagiri

Jichi Medical School: Hiroaki Watanabe

JCHO Yamato Koriyama Hospital: Tetsuhisa Hattori

Saiseikai Kyoto Hospital: Kazuya Ishibashi

Fujita Health University Hospital: Eiichi Watanabe

Showa University Fujigaoka Hospital: Daisuke Wakatsuki, Yukei Higashi

Japanese Red Cross Otsu Hospital: Hirooki Higami, Takashi Konishi (in order of descending

subject prevalence)

Sense (5' to 3')

CCCAGATCCCGAGGTCCGAC

TGCCCTCTCCTGGTAATTGC

CCTTCCAGTTCTTGTGTTCTGTGAC

GGCCTCCCAGGAACTAATTCTG

GCAGTGATGCCCAACTCAGG

GCCAAGACTATGTTTAGAGCTTG

AGTGTCCTCTGGCCGGCAAC

GAGGCCTCAATTGCAGGCAGGC

GTAAGCAGCAGGCCGGACAAAG

GGAGCCTGCAGGAGCCTGGAGC

CTTGTCTGAGCCCCAGACTGGAG

8-9

Oligonucleotide primers of PCR amplifying LMNA

Exon

Table S1.

AGGGAAAAGGAAGGGAGGAGAAAT

GCTGCGGAAGAGAAGGCAGGCTC

CACAGGAATATTCCATGGCATC

CTCGTCCAGCAAGCAGCCAG

TCACCCTGGTCCACCCTCTG

GGTCTAGTCAAGGCCAGTTG

TGCATCCGGCCCAGACTCTA

CTCCCTGCCACCATCTGC

CCTAGCCCAGCCCAAGTCTGTC

AGGGCCTAGGTAGAAGAGTG

CCTCTCCACTCCCCGCCA

Antisense (3' to 5')

436

465

459

452

400

466

257

334

250

352

574

Product (bp)

Annealing (

E223G

F237C

Q312H

668A>G

959T>G

936G>C

591

0/853

0/990

0/1089

rs794728 0/1086

R216C

646C>T

0/1072,

0/1100

0/1077

L197P

E115M

[343G>A;344A

0/1098

590T>C§

E112A

335A>C§

0/1092

KyotoDB)

(HGVD,

MAF

0/1070

Q36L

107A>T

dbSNP

>T]§

P20L

protein

59C>T

codon

LMNA gene mutation

ExAC

In silico bioinformatic information of 16 missense mutations

Table S2.

of pathogenicity

interpretations

Conflicting

ClinVar

DAMAGING,

damaging

0.96/probably

DAMAGING,

damaging

0.847/probably

DAMAGING,

0.996/probably

damaging

DAMAGING,

0.01

damaging

0.962/probably

DAMAGING,

0.05

0.891/probably

damaging

DAMAGING,

damaging

0.999/probably

DAMAGING,

0.1

damaging

0.772/probably

DAMAGING,

damaging

0.842/probably

DAMAGING,

SIFT

0.984/probably

PP2

941685

Deleterious,0.648

118982321

Deleterious,0.595

944714

Deleterious,0.540

111646

Deleterious,0.618

260076772

Deleterious,0.634

292542996

Deleterious,0.568

286467119

Deleterious,0.676

857153013

Deleterious,0.595

Condel

negative

prediction

splice site

Q353R

D357H

M371R

R377C

T496S

A577T

1058A>G

1069G>C

1112T>G

1129C>T

1486A>T§

1729G>A§

0/1101

0/1078

0/1101

889

0/865

1/1102

rs397517 0/1101

567

rs267607 0/1101

4243

rs38613

ly pathogenic

Pathogenic/Like

not provided

ly pathogenic

Pathogenic/Like

Neutral,0.510797

817

0.03

975169

Deleterious,0.645

63497504

Deleterious,0.665

77859357

Deleterious,0.658

178837

DAMAGING,

0.01

damaging

0.273/ benign

DAMAGING,

0.998/ probably

damaging

DAMAGING,

damaging

1/probably

DAMAGING,

0.07

0.947/probably

damaging

732445

Deleterious,0.630

249193

Deleterious,0.672

TOLERATED, Deleterious,0.525

0.01

damaging

0.995/probably

DAMAGING,

0.71/possibly

damaging

0.962/probably

negative

Variation Database; LMNA = lamin A/C gene; MAF = minor allele frequency; na = not available.

Condel (http://bg.upf.edu/fannsdb/); splice site prediction tool (Berkeley Drosophila Genome Project: http://www.fruitfly.org). HGV = Human Genetic

(http://exac.broadinstitute.org); ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); Polyphen 2 (http://genetics.bwh.harvard.edu/pph2/); SIFT (http://sift.jcvi.org/);

‘classification, score’. dbSNP build 146 database (http://www.ncbi.nlm.nih.gov/projects/SNP/); HGV (http://www.genome.med.kyoto-u.ac.jp/SnpDB/); ExAC

Novel mutations are indicated by boldface. §: variant excluded because of unknown significance. Results by in silico predictions were expressed as

R335W

1003C>T

Table S3.

Clinical characteristics of 45 Probands at first clinical contact

Total

Truncation

Missense

n = 45

n = 31

n = 14

46.3 ± 12.9

52.2 ± 13.6

0.17

21 (68)

10 (71)

1.0

6 (19)

1 (7)

0.41

6 (19)

2 (14)

1.0

atrial arrhythmia

20 (65)

7 (50)

0.51

ventricular arrhythmia

12 (39)

4 (29)

0.73

CCD

22 (71)

11 (79)

0.73

SSS

7 (23)

3 (21)

1.0

AV block ( 1)

18 (58)

8 (57)

1.0

LVEF<50%

18 (58)

3 (21)

0.028

LV enlargement

14 (45)

4 (29)

0.34

Coronary artery disease

2 (6)

0 (0)

1.0

Hypertension

5 (16)

3 (21)

0.69

Diabetic mellitus

0 (0)

PM implantation

6 (19)

3 (21)

1.0

ICD/CRTD implantation

3 (10)

0 (0)

0.54

Anticoagulant

12 (39)

3 (21)

0.32

Beta-blocker

10 (32)

4 (29)

1.0

ACEI inhibitor or ARB

13 (42)

6 (43)

1.0

Age, yrs

Male

p value

Symptom

Syncope

NYHA classification

Arrhythmia

Cardiomyopathy

Comorbidities

Medication

Number of subjects is expressed as n(%). Continuous variables are shown as mean ± standard deviation. ;

CCD = cardiac conduction disturbance; CRTD = cardiac resynchronization therapy defibrillator; SSS = sick

sinus syndrome; AV block = atrio-ventricular block; LV = left ventricular; EF = ejection fraction; PM =

pacemaker; ICD = implantable cardioverter defibrillator; ACE-I = angiotensin-converting enzyme inhibitor;

ARB = angiotensin receptor blocker; VF = ventricular fibrillation

Table S4.

Clinical characteristics of 45 Probands at last follow-up

Total

n=45

Truncation

n = 31

50.5±12.7

21 (68)

Missense

n = 14

57.7±14.3

10 (71)

p value

Age, yrs

0.048

Male

1.0

Family history

SCD

14 (45)

3 (21)

0.19

heart failure

10 (32)

3 (21)

0.72

CCD

21 (68)

10 (71)

1.0

Symptom

syncope

9(29)

3(21)

0.73

NYHA classification 3

12(39)

6(43)

1.0

Arrhythmia

atrial arrhythmia

27(87)

7(50)

0.02

ventricular arrhythmia

19(61)

8(57)

1.0

CCD

27 (87)

11 (79)

0.66

SSS

10 (32)

3 (21)

0.72

AV block ( 1)

23 (74)

8 (57)

0.31

Cardiomyopathy

LVEF<50%

24(77)

5(36)

0.016

LV enlargement

17(55)

9(64)

0.75

Comorbidities

Coronary artery disease

2(6)

0(0)

1.0

Hypertension

6(19)

3(21)

1.0

Diabetic mellitus

0(0)

1(7)

0.31

PM implantation

7(23)

4(29)

0.72

ICD/CRTD implantation

17(55)

8(57)

1.0

Medication

Anticoagulant

13(42)

6(43)

1.0

Beta-blocker

13(42)

7(50)

0.75

ACEI inhibitor or ARB

15(48)

5(36)

0.53

Major cardiac events

VF/sustained VT

13(42)

2(14)

0.09

Appropriate ICD shock

5(16)

0(0)

0.30

Cardiopulmonary resuscitation

2(6)

0(0)

1.0

All-cause death

7(23)

1(7)

0.40

Death due to end-stage heart failure 6

5(16)

1(7)

0.65

SCD

2(6)

0(0)

1.0

Number of subjects is expressed as n (%). Continuous variables are shown as mean ± standard deviation.

SCD = sudden cardiac death; CCD = cardiac conduction disturbance; CRTD = cardiac resynchronization

therapy with defibrillator; SSS = sick sinus syndrome; AV block = atrio-ventricular block; LV = left

ventricular; EF = ejection fraction; PM = pacemaker; ICD = implantable cardioverter defibrillator; ACE-I =

angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; VF = ventricular fibrillation

Supplemental Figure

Figure S1

Comparison of age at the onset of major cardiac phenotypes in 77 LMNA mutation carriers

between probands and their relatives (blank triangle: probands vs. solid triangle: relatives).

CCD = cardiac conduction disturbance; AA = atrial arrhythmias; LVEF = left ventricular

ejection fraction.

Figure S2

Comparison of age at the onset of major cardiac phenotypes in 77 LMNA mutation carriers

between with NLS-conserved residue (blank inverted triangle) and NLS-disturbed residue

(solid inverted triangle:). CCD = cardiac conduction disturbance; AA = atrial arrhythmias;

LVEF = left ventricular ejection fraction; NLS = nuclear localization signal.

Figure S3

Comparison of age at the onset of major cardiac phenotypes in 77 LMNA mutation carriers

by gender (blank circle: female vs. solid circle: male). CCD = cardiac conduction

disturbance; AA = atrial arrhythmias; LVEF = left ventricular ejection fraction.

...

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Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers

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