Lamin A/C-Related Cardiac Disease Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation

Edgar T. Hoorntje; Ilse A. Bollen; Daniela Q. Barge-Schaapveld; Florence H. van Tienen; Gerard J. te Meerman; Joeri A. Jansweijer; Anthonie J. van Essen; Paul G. Volders; Alina A. Constantinescu; Peter C. van den Akker; Karin Y. van Spaendonck-Zwarts; Rogier A. Oldenburg; Carlo L. Marcelis; Jasper J. van der Smagt; Eric A. Hennekam; Aryan Vink; Marianne Bootsma; Emmelien Aten; Arthur A. Wilde; Arthur van den Wijngaard; Jos L. Broers; Jan D. Jongbloed; Jolanda van der Velden; Maarten P. van den Berg; J. Peter van Tintelen

doi:10.1161/CIRCGENETICS.116.001631

Lamin A/C-Related Cardiac Disease Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation

Edgar T. Hoorntje, Ilse A. Bollen, Daniela Q. Barge-Schaapveld, Florence H. van Tienen, Gerard J. te Meerman, Joeri A. Jansweijer, Anthonie J. van Essen, Paul G. Volders, Alina A. Constantinescu, Peter C. van den Akker, Karin Y. van Spaendonck-Zwarts, Rogier A. Oldenburg, Carlo L. Marcelis, Jasper J. van der Smagt, Eric A. Hennekam, Aryan Vink, Marianne Bootsma, Emmelien Aten, Arthur A. Wilde, Arthur van den WijngaardJos L. Broers, Jan D. Jongbloed, Jolanda van der Velden, Maarten P. van den Berg, J. Peter van Tintelen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background-Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies.

Methods and Results-Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy.

Conclusions-Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations but with a more benign course.

Original language	English
Article number	001631
Number of pages	36
Journal	Circulation : Cardiovascular Genetics
Volume	10
Issue number	4
DOIs	https://doi.org/10.1161/CIRCGENETICS.116.001631
Publication status	Published - Aug 2017

Keywords

atrial fibrillation
atrioventricular block
cardiomyopathy, dilated
lipodystrophy
survival
IDIOPATHIC DILATED CARDIOMYOPATHY
RIGHT-VENTRICULAR CARDIOMYOPATHY
324 UNRELATED PATIENTS
GENE-MUTATIONS
ATRIOVENTRICULAR-BLOCK
MISSENSE MUTATIONS
SUDDEN-DEATH
LMNA CAUSES
HIGH-RISK
SCN5A

Access to Document

10.1161/CIRCGENETICS.116.001631

Cite this

Hoorntje, E. T., Bollen, I. A., Barge-Schaapveld, D. Q., van Tienen, F. H., te Meerman, G. J., Jansweijer, J. A., van Essen, A. J., Volders, P. G., Constantinescu, A. A., van den Akker, P. C., van Spaendonck-Zwarts, K. Y., Oldenburg, R. A., Marcelis, C. L., van der Smagt, J. J., Hennekam, E. A., Vink, A., Bootsma, M., Aten, E., Wilde, A. A., ... van Tintelen, J. P. (2017). Lamin A/C-Related Cardiac Disease Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation. Circulation : Cardiovascular Genetics, 10(4), Article 001631. https://doi.org/10.1161/CIRCGENETICS.116.001631

@article{bbe3966a3537421ea8b0b53758935895,

title = "Lamin A/C-Related Cardiac Disease Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation",

abstract = "Background-Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies.Methods and Results-Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy.Conclusions-Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations but with a more benign course.",

keywords = "atrial fibrillation, atrioventricular block, cardiomyopathy, dilated, lipodystrophy, survival, IDIOPATHIC DILATED CARDIOMYOPATHY, RIGHT-VENTRICULAR CARDIOMYOPATHY, 324 UNRELATED PATIENTS, GENE-MUTATIONS, ATRIOVENTRICULAR-BLOCK, MISSENSE MUTATIONS, SUDDEN-DEATH, LMNA CAUSES, HIGH-RISK, SCN5A",

author = "Hoorntje, {Edgar T.} and Bollen, {Ilse A.} and Barge-Schaapveld, {Daniela Q.} and {van Tienen}, {Florence H.} and {te Meerman}, {Gerard J.} and Jansweijer, {Joeri A.} and {van Essen}, {Anthonie J.} and Volders, {Paul G.} and Constantinescu, {Alina A.} and {van den Akker}, {Peter C.} and {van Spaendonck-Zwarts}, {Karin Y.} and Oldenburg, {Rogier A.} and Marcelis, {Carlo L.} and {van der Smagt}, {Jasper J.} and Hennekam, {Eric A.} and Aryan Vink and Marianne Bootsma and Emmelien Aten and Wilde, {Arthur A.} and {van den Wijngaard}, Arthur and Broers, {Jos L.} and Jongbloed, {Jan D.} and {van der Velden}, Jolanda and {van den Berg}, {Maarten P.} and {van Tintelen}, {J. Peter}",

year = "2017",

month = aug,

doi = "10.1161/CIRCGENETICS.116.001631",

language = "English",

volume = "10",

journal = "Circulation : Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams & Wilkins",

number = "4",

}

Hoorntje, ET, Bollen, IA, Barge-Schaapveld, DQ, van Tienen, FH, te Meerman, GJ, Jansweijer, JA, van Essen, AJ, Volders, PG, Constantinescu, AA, van den Akker, PC, van Spaendonck-Zwarts, KY, Oldenburg, RA, Marcelis, CL, van der Smagt, JJ, Hennekam, EA, Vink, A, Bootsma, M, Aten, E, Wilde, AA, van den Wijngaard, A, Broers, JL, Jongbloed, JD, van der Velden, J, van den Berg, MP & van Tintelen, JP 2017, 'Lamin A/C-Related Cardiac Disease Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation', Circulation : Cardiovascular Genetics, vol. 10, no. 4, 001631. https://doi.org/10.1161/CIRCGENETICS.116.001631

Lamin A/C-Related Cardiac Disease Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation. / Hoorntje, Edgar T.; Bollen, Ilse A.; Barge-Schaapveld, Daniela Q. et al.
In: Circulation : Cardiovascular Genetics, Vol. 10, No. 4, 001631, 08.2017.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Lamin A/C-Related Cardiac Disease Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation

AU - Hoorntje, Edgar T.

AU - Bollen, Ilse A.

AU - Barge-Schaapveld, Daniela Q.

AU - van Tienen, Florence H.

AU - te Meerman, Gerard J.

AU - Jansweijer, Joeri A.

AU - van Essen, Anthonie J.

AU - Volders, Paul G.

AU - Constantinescu, Alina A.

AU - van den Akker, Peter C.

AU - van Spaendonck-Zwarts, Karin Y.

AU - Oldenburg, Rogier A.

AU - Marcelis, Carlo L.

AU - van der Smagt, Jasper J.

AU - Hennekam, Eric A.

AU - Vink, Aryan

AU - Bootsma, Marianne

AU - Aten, Emmelien

AU - Wilde, Arthur A.

AU - van den Wijngaard, Arthur

AU - Broers, Jos L.

AU - Jongbloed, Jan D.

AU - van der Velden, Jolanda

AU - van den Berg, Maarten P.

AU - van Tintelen, J. Peter

PY - 2017/8

Y1 - 2017/8

N2 - Background-Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies.Methods and Results-Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy.Conclusions-Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations but with a more benign course.

AB - Background-Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies.Methods and Results-Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy.Conclusions-Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations but with a more benign course.

KW - atrial fibrillation

KW - atrioventricular block

KW - cardiomyopathy, dilated

KW - lipodystrophy

KW - survival

KW - IDIOPATHIC DILATED CARDIOMYOPATHY

KW - RIGHT-VENTRICULAR CARDIOMYOPATHY

KW - 324 UNRELATED PATIENTS

KW - GENE-MUTATIONS

KW - ATRIOVENTRICULAR-BLOCK

KW - MISSENSE MUTATIONS

KW - SUDDEN-DEATH

KW - LMNA CAUSES

KW - HIGH-RISK

KW - SCN5A

U2 - 10.1161/CIRCGENETICS.116.001631

DO - 10.1161/CIRCGENETICS.116.001631

M3 - Article

C2 - 28790152

SN - 1942-325X

VL - 10

JO - Circulation : Cardiovascular Genetics

JF - Circulation : Cardiovascular Genetics

IS - 4

M1 - 001631

ER -

Lamin A/C-Related Cardiac Disease Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation

Abstract

Keywords

Access to Document

Fingerprint

Cite this