Mutations in the sarcomere gene MYH7 in Ebstein anomaly.
BACKGROUND
Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. An association between Ebstein anomaly with left ventricular noncompaction (LVNC) and mutations in MYH7 encoding β-myosin heavy chain has been shown; in this report, we have screened for MYH7 mutations in a cohort of probands with Ebstein anomaly in a large population-based study.


RESULTS
Mutational analysis in a cohort of 141 unrelated probands with Ebstein anomaly was performed by next-generation sequencing and direct DNA sequencing of MYH7. Heterozygous mutations were identified in 8 of 141 samples (6%). Seven distinct mutations were found; 5 were novel and 2 were known to cause hypertrophic cardiomyopathy. All mutations except for 1 3-bp deletion were missense mutations; 1 was a de novo change. Mutation-positive probands and family members showed various congenital heart malformations as well as LVNC. Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC. The frequency of MYH7 mutations was significantly different between probands with and without LVNC accompanying Ebstein anomaly (P<0.0001). LVNC segregated with the MYH7 mutation in the pedigrees of 3 of the probands, 1 of which also included another individual with Ebstein anomaly.


CONCLUSIONS
Ebstein anomaly is a congenital heart malformation that is associated with mutations in MYH7. MYH7 mutations are predominantly found in Ebstein anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients.
Heart Failure Research Center, the Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, The Netherlands.
Alex V
AV
Postma
Klaartje
K
van Engelen
Judith
J
van de Meerakker
Thahira
T
Rahman
Susanne
S
Probst
Marieke J H
MJ
Baars
Ulrike
U
Bauer
Thomas
T
Pickardt
Silke R
SR
Sperling
Felix
F
Berger
Antoon F M
AF
Moorman
Barbara J M
BJ
Mulder
Ludwig
L
Thierfelder
Bernard
B
Keavney
Judith
J
Goodship
Sabine
S
Klaassen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D024722:Cardiac Myosins / Q000737:chemistry / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004437:Ebstein Anomaly / Q000000981:diagnostic imaging / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D012518:Sarcomeres / Q000235:genetics*; D014463:Ultrasonography; D055815:Young Adult
C501641:MYH7 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains