The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy.
BACKGROUND
Left ventricular (LV) noncompaction (LVNC) is a distinct cardiomyopathy featuring a thickened bilayered LV wall consisting of a thick endocardial layer with prominent intertrabecular recesses with a thin, compact epicardial layer. Similar to hypertrophic and dilated cardiomyopathy, LVNC is genetically heterogeneous and was recently associated with mutations in sarcomere genes. To contribute to the genetic classification for LVNC, a systematic cardiological family study was performed in a cohort of 58 consecutively diagnosed and molecularly screened patients with isolated LVNC (49 adults and 9 children).


RESULTS
Combined molecular testing and cardiological family screening revealed that 67% of LVNC is genetic. Cardiological screening with electrocardiography and echocardiography of 194 relatives from 50 unrelated LVNC probands revealed familial cardiomyopathy in 32 families (64%), including LVNC, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Sixty-three percent of the relatives newly diagnosed with cardiomyopathy were asymptomatic. Of 17 asymptomatic relatives with a mutation, 9 had noncompaction cardiomyopathy. In 8 carriers, nonpenetrance was observed. This may explain that 44% (14 of 32) of familial disease remained undetected by ascertainment of family history before cardiological family screening. The molecular screening of 17 genes identified mutations in 11 genes in 41% (23 of 56) tested probands, 35% (17 of 48) adults and 6 of 8 children. In 18 families, single mutations were transmitted in an autosomal dominant mode. Two adults and 2 children were compound or double heterozygous for 2 different mutations. One adult proband had 3 mutations. In 50% (16 of 32) of familial LVNC, the genetic defect remained inconclusive.


CONCLUSIONS
LVNC is predominantly a genetic cardiomyopathy with variable presentation ranging from asymptomatic to severe. Accordingly, the diagnosis of LVNC requires genetic counseling, DNA diagnostics, and cardiological family screening.
Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
Yvonne M
YM
Hoedemaekers
Kadir
K
Caliskan
Michelle
M
Michels
Ingrid
I
Frohn-Mulder
Jasper J
JJ
van der Smagt
Judith E
JE
Phefferkorn
Marja W
MW
Wessels
Folkert J
FJ
ten Cate
Eric J G
EJ
Sijbrands
Dennis
D
Dooijes
Danielle F
DF
Majoor-Krakauer
D000293:Adolescent; D000328:Adult; D024722:Cardiac Myosins / Q000235:genetics; D009202:Cardiomyopathies / Q000175:diagnosis* / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005817:Genetic Counseling; D005838:Genotype; D006352:Heart Ventricles; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics; D010375:Pedigree; D012518:Sarcomeres / Q000235:genetics; D000099163:Myosin Binding Protein C
D024722:Cardiac Myosins; D002352:Carrier Proteins; D018995:Myosin Heavy Chains; D000099163:Myosin Binding Protein C; C501641:MYH7 protein, human