Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers.
Phenotypic heterogeneity and incomplete penetrance are common in patients with hypertrophic cardiomyopathy (HCM). We aim to improve the understanding in genotype-phenotype correlations in HCM, particularly the contribution of an MYL2 founder mutation and risk factors to left ventricular hypertrophic remodelling.



We analysed 14 HCM families of whom 38 family members share the MYL2 c.64G > A [p.(Glu22Lys)] mutation and a common founder haplotype. In this unique cohort, we investigated factors influencing phenotypic outcome in addition to the primary mutation. The mutation alone showed benign disease manifestation with low penetrance. The co-presence of additional risk factors for hypertrophy such as hypertension, obesity, or other sarcomeric gene mutation increased disease penetrance substantially and caused HCM in 89% of MYL2 mutation carriers (P = 0.0005). The most prominent risk factor was hypertension, observed in 71% of mutation carriers with HCM and an additional risk factor.



The MYL2 mutation c.64G > A on its own is incapable of triggering clinical HCM in most carriers. However, the presence of an additional risk factor for hypertrophy, particularly hypertension, adds to the development of HCM. Early diagnosis of risk factors is important for early treatment of MYL2 mutation carriers and close monitoring should be guaranteed in this case. Our findings also suggest that the presence of hypertension or another risk factor for hypertrophy should not be an exclusion criterion for genetic studies.
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands lieve.claes@mumc.nl.
Godelieve R F
GR
Claes
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands.
Florence H J
FH
van Tienen
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands.
Patrick
P
Lindsey
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands.
Ingrid P C
IP
Krapels
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands.
Apollonia T J M
AT
Helderman-van den Enden
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands.
Marije B
MB
Hoos
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands.
Yvette E G
YE
Barrois
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands.
Johanna W H
JW
Janssen
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands.
Aimée D C
AD
Paulussen
Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands Department of Intensive Care, Maastricht University Medical Centre, Maastricht, The Netherlands.
Jan-Willem E M
JW
Sels
Department of Cardiology, Máxima Medical Centre, Eindhoven, The Netherlands.
Simone H H
SH
Kuijpers
Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
J Peter
JP
van Tintelen
Department of Cardiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
Maarten P
MP
van den Berg
Department of Cardiology, VieCuri Medical Centre, Venlo, The Netherlands.
Wilfred F
WF
Heesen
Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
Pablo
P
Garcia-Pavia
Charité-Universitätsmedizin Berlin, Experimental & Clinical Research Centre, A Joint Cooperation Between the Charité Medical Faculty and the Max-Delbrück Centre for Molecular Medicine, Berlin, Germany.
Andreas
A
Perrot
Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
Imke
I
Christiaans
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
Simone
S
Salemink
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
Carlo L M
CL
Marcelis
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands.
Hubert J M
HJ
Smeets
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
Han G
HG
Brunner
Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.
Paul G A
PG
Volders
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, P.O. Box 5800, 6229 GR Maastricht, The Netherlands School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands.
Arthur
A
van den Wijngaard
D024722:Cardiac Myosins / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005858:Germany / Q000453:epidemiology; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000401:mortality; D017379:Hypertrophy, Left Ventricular / Q000235:genetics* / Q000401:mortality; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D018994:Myosin Light Chains / Q000235:genetics*; D020257:Ventricular Remodeling / Q000235:genetics
D018994:Myosin Light Chains; C107184:myosin light chain 2; D024722:Cardiac Myosins
Genetics; Hypertension; Hypertrophic cardiomyopathy; Hypertrophy; Mutation; Risk factors