Alternative titles; symbols
ORPHA: 54260; DO: 0060480;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q12.1 | Left ventricular noncompaction 1, with or without congenital heart defects | 604169 | Autosomal dominant | 3 | DTNA | 601239 |
A number sign (#) is used with this entry because of evidence that left ventricular noncompaction-1 (LVNC1) is caused by a heterozygous mutation in the alpha-dystrobrevin gene (DTNA; 601239) on chromosome 18q12.
Left ventricular noncompaction (LVNC) is characterized by numerous prominent trabeculations and deep intertrabecular recesses in hypertrophied and hypokinetic segments of the left ventricle (Sasse-Klaassen et al., 2004). The mechanistic basis is thought to be an intrauterine arrest of myocardial development with lack of compaction of the loose myocardial meshwork. LVNC may occur in isolation or in association with congenital heart disease. Distinctive morphologic features can be recognized on 2-dimensional echocardiography (Kurosaki et al., 1999). Noncompaction of the ventricular myocardium is sometimes referred to as spongy myocardium. Stollberger et al. (2002) commented that the term 'isolated LVNC,' meaning LVNC without coexisting cardiac abnormalities, is misleading, because additional cardiac abnormalities are found in nearly all patients with LVNC.
Genetic Heterogeneity of Left Ventricular Noncompaction
A locus for autosomal dominant left ventricular noncompaction has been identified on chromosome 11p15 (LVNC2; 609470).
LVNC3 (see 605906) is caused by mutation in the LDB3 gene (605906) on chromosome 10q23. LVNC4 (see 613424) is caused by mutation in the ACTC1 gene (102540) on chromosome 15q14. LVNC5 (see 613426) is caused by mutation in the MYH7 gene (160760) on chromosome 14q12. LVNC6 (see 601494) is caused by mutation in the TNNT2 gene (191045) on chromosome 1q32. LVNC7 (615092) is caused by mutation in the MIB1 gene (608677) on chromosome 18q11. LVNC8 (615373) is caused by mutation in the PRDM16 gene (605557) on chromosome 1p36. LVNC9 (see 611878) is caused by mutation in the TPM1 gene (191010) on chromosome 15q22. LVNC10 (615396) is caused by mutation in the MYBPC3 gene (600958) on chromosome 11p11.
LVNC can also occur as part of an X-linked disorder, Barth syndrome (302060), caused by mutation in the TAZ gene (300394) on chromosome Xq28.
Although left ventricular noncompaction (LVNC) has been classified as a primary genetic cardiomyopathy by the American Heart Association (Maron et al., 2006), Monserrat et al. (2007) stated that it is controversial whether LVNC should be considered a distinct cardiomyopathy or rather a phenotypic variant of other primary cardiomyopathies, noting that patients fulfilling echocardiographic criteria for LVNC may have associated phenotypes of dilated cardiomyopathy (see CMD1A, 115200), hypertrophic cardiomyopathy (see CMH1, 192600), or restrictive cardiomyopathy (see RCM1, 115210). Monserrat et al. (2007) concluded that with current diagnostic criteria, LVNC, CMH, RCM, and even CMD could appear as overlapping entities, and should not be considered mutually exclusive.
Chin et al. (1990) described the echocardiographic characteristics of left ventricular noncompaction in 8 patients, 5 males and 3 females. Clinical manifestations of the disorder included depressed left ventricular systolic function in 5 patients, ventricular arrhythmias in 5, systemic embolization in 3, and distinctive facial dysmorphism in 3. Among the 5 male patients, there were 2 sets of brothers from 2 unrelated families.
Cao et al. (2017) reported a 39-year-old man with a diagnosis of LVNC who had a history of exercise-related chest distress and palpitation for 8 years without a family history of sudden cardiac death. Transthoracic echocardiography showed prominent trabeculations and intertrabecular recesses in the apex of the left ventricle, with a 17-mm uncompacted layer versus a 7-mm compacted layer. The end-diastolic diameter of the left ventricle was 80 mm. Diffuse hypokinesis was present with a left ventricular ejection fraction (LVEF) of 34%. ECG showed a first-degree atrioventricular block.
Patients without an Identified Mutation
Kurosaki et al. (1999) described a possibly autosomal dominant form of isolated noncompaction of the left ventricular myocardium. The proband was a 58-year-old male. His parents were cousins, and both died of cerebral infarction. It was unknown whether or not they had suffered from heart disease. The proband had had recent onset of faintness and palpitation. His nose was flat and upturned, similar to a saddle nose. Electrocardiography showed first-degree atrioventricular block and complete right bundle branch block. On 2-dimensional echocardiography, the main abnormality consisted of prominent trabeculations of the left ventricular apex with deep intertrabecular spaces. Physical and electrocardiographic examinations were performed in 9 of 17 members of 3 generations of the family, and 2-dimensional and Doppler echocardiography were performed in those members who showed characteristic facial dysmorphism or electrocardiographic abnormalities. In this way, noncompaction of the left ventricular myocardium was diagnosed in 4 other members of the family. The proband's older brother was seen at the age of 48 years for palpitation and shortness of breath. Electrocardiography showed normal sinus rhythm with left bundle branch block, which developed into chronic atrial fibrillation in later years. Nonsustained ventricular tachycardia and sinus arrest for 7.9 seconds were detected by Holter electrocardiography. At the age of 52 and 56, he suffered small episodes of cerebral embolism. He died of progressive congestive heart failure at the age of 59 years. Autopsy showed trabeculations at the apex of the left ventricle. This man's son, at the age of 31, showed no facial dysmorphism, but electrocardiography showed incomplete right bundle branch block and 2-dimensional echocardiography showed systolic left ventricular dysfunction with prominent trabeculations in the apical portion. The proband's son, at the age of 30, showed normal left ventricular contraction with marked trabeculations at the apex and blood flow within intertrabecular spaces, on echocardiography.
Reviews
Ichida (2009) reviewed the clinical features and genetics of left ventricular noncompaction, noting that it was first described in 1990. The clinical presentation is highly variable, ranging from asymptomatic to severe heart failure and sudden death. Higher occurrence of familial cases, facial dysmorphism, and congenital arrhythmias such as Wolff-Parkinson-White syndrome (see 194200) are observed in children, whereas secondary arrhythmias, such as atrial fibrillation, are more common in adults. The mode of inheritance is predominantly autosomal dominant, and sarcomere protein mutations are more common in adults. Ichida (2009) suggested that there may be a different underlying etiology between childhood and adult cases. In addition, noting the high incidence of LVNC in adults, Ichida (2009) suggested that hypertrabeculation may occur secondary to other events and that LVNC may be overdiagnosed because of sensitive diagnostic criteria, which should be reappraised.
The developing myocardium gradually condenses, and the large spaces within the trabecular meshwork flatten or disappear. Isolated noncompaction of ventricular myocardium, sometimes called spongy myocardium or persisting myocardial sinusoids, represents an arrest in endomyocardial morphogenesis, and is characterized by numerous, excessively prominent trabeculations and deep intertrabecular recesses (Chin et al., 1990).
Pauli et al. (1999) described a 7.5-year-old girl with a complex heart malformation including ventricular myocardial noncompaction. She was found to have a distal 5q deletion, del(5)(q35.1-q35.3). FISH showed that this deletion included the locus for the cardiac-specific homeobox gene CSX (600584). Pauli et al. (1999) interpreted the findings to suggest that in some instances ventricular myocardial noncompaction can be caused by haploinsufficiency of CSX.
Autosomal dominant transmission of ventricular noncompaction was suggested by the families reported by Hamamichi et al. (1996), Ritter et al. (1997), and Sasse-Klaassen et al. (2003). Two pairs of sibs reported by Hamamichi et al. (1996) were cousins, and their fathers were brothers. Ritter et al. (1997) described an affected father and daughter. In addition to the 4 female patients observed in these 2 families, Matsuda et al. (1999) pointed to 10 female patients without familial occurrence but with clinical manifestations similar to those of a total of 33 male patients.
In affected members of a 4-generation Japanese family with left ventricular noncompaction, Ichida et al. (2001) identified a missense mutation in the DTNA gene (P121L; 601239.0001). Of the 6 individuals with LVNC, only 1 had no other congenital heart defects; the other 5 all had at least 1 ventricular septal defect, and 1 patient also had a patent ductus arteriosus, another had hypoplastic left ventricle, and another died with a hypoplastic left heart. In a second Japanese family with LVNC and congenital heart defects in which a mother and 2 daughters were affected, no mutation in alpha-dystrobrevin or in the X-linked TAZ gene (300394) was found by Ichida et al. (2001).
In a 39-year-old man with a diagnosis of LVNC, in whom mutations in 8 candidate genes were excluded, Cao et al. (2017) identified a heterozygous missense mutation in the DTNA gene (N49S; 601239.0002) by Sanger sequencing. The mutation was not found in the NHLBI ESP or 1000 Genomes Project databases or in 400 ethnically matched controls. A cardiac-specific transgenic mouse model that overexpressed Dtna with the N49S mutation was found to have a progressive cardiomyopathy characterized by dilated and thinner LV, cardiac systolic dysfunction, and age-related LV hypertrabeculation.
Probst et al. (2011) reported a cohort of 63 LVNC probands, previously studied by Klaassen et al. (2008), in which 8 sarcomere genes were analyzed and heterozygous mutations found in 18 (29%) of the probands: 8 mutations were in the MYH7 gene, 5 in MYBPC3, 2 in ACTC1, 2 in TPM1, and 1 in TNNT2. There were no significant differences between mutation-positive and mutation-negative probands in terms of average age, myocardial function, or presence of heart failure or tachyarrythmias at initial presentation or at follow-up. Probst et al. (2011) noted that although 8 of the 15 distinct mutations were novel in this cohort, they were likely not specific to LVNC, because the other 7 mutations had previously been described in patients with other forms of cardiomyopathy, including hypertrophic (see CMH1, 192600) and dilated (see CMD1A, 115200) forms.
Isolated noncompaction of left ventricular myocardium is observed in mice in which the FK506-binding protein-1A gene (FKBP1A; 186945) has been 'knocked out' by embryonic stem cell technology. The FKBP1A gene maps to 20p13.
Cao, Q., Shen, Y., Liu, X., Yu, X., Yuan, P., Wan, R., Liu, X., Peng, X., He, W., Pu, J., Hong, K. Phenotype and functional analyses in a transgenic mouse model of left ventricular noncompaction caused by a DTNA mutation. Int. Heart J. 58: 939-947, 2017. [PubMed: 29118297] [Full Text: https://doi.org/10.1536/ihj.16-019]
Chin, T. K., Perloff, J. K., Williams, R. G., Jue, K., Mohrmann, R. Isolated noncompaction of left ventricular myocardium: a study of eight cases. Circulation 82: 507-513, 1990. [PubMed: 2372897] [Full Text: https://doi.org/10.1161/01.cir.82.2.507]
Hamamichi, Y., Kamiya, T., Singaki, Y., Ono, Y., Echigo, S., Tanada, I., Takamiya, M., Iida, K., Yamatani, C., Naito, H. Familial occurrence with isolated noncompaction of the myocardium. (Abstract) Acta Cardiol. Paediat. Jpn. 12: 220 only, 1996.
Ichida, F., Tsubata, S., Bowles, K. R., Haneda, N., Uese, K., Miyawaki, T., Dreyer, W. J., Messina, J., Li, H., Bowles, N. E., Towbin, J. A. Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation 103: 1256-1263, 2001. [PubMed: 11238270] [Full Text: https://doi.org/10.1161/01.cir.103.9.1256]
Ichida, F. Left ventricular noncompaction. Circ. J. 73: 19-26, 2009. [PubMed: 19057090] [Full Text: https://doi.org/10.1253/circj.cj-08-0995]
Klaassen, S., Probst, S., Oechslin, E., Gerull, B., Krings, G., Schuler, P., Greutmann, M., Hurlimann, D., Yegibasi, M., Pons, L., Gramlich, M., Drenckhahn, J.-D., Heuser, A., Berger, F., Jenni, R., Thierfelder, L. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation 117: 2893-2901, 2008. [PubMed: 18506004] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.746164]
Kurosaki, K., Ikeda, U., Hojo, Y., Fujikawa, H., Katsuki, T., Shimada, K. Familial isolated noncompaction of the left ventricular myocardium. Cardiology 91: 69-72, 1999. [PubMed: 10393402] [Full Text: https://doi.org/10.1159/000006880]
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Monserrat, L., Hermida-Prieto, M., Fernandez, X., Rodriguez, I., Dumont, C., Cazon, L., Cuesta, M. G., Gonzalez-Juanatey, C., Peteiro, J., Alvarez, N., Penas-Lado, M., Castro-Beiras, A. Mutation in the alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular non-compaction, and septal defects. Europ. Heart J. 28: 1953-1961, 2007. [PubMed: 17611253] [Full Text: https://doi.org/10.1093/eurheartj/ehm239]
Pauli, R. M., Scheib-Wixted, S., Cripe, L., Izumo, S., Sekhon, G. S. Ventricular noncompaction and distal chromosome 5q deletion. Am. J. Med. Genet. 85: 419-423, 1999. [PubMed: 10398271]
Probst, S., Oechslin, E., Schuler, P., Greutmann, M., Boye, P., Knirsch, W., Berger, F., Thierfelder, L., Jenni, R., Klaassen, S. Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype. Circ. Cardiovasc. Genet. 4: 367-374, 2011. [PubMed: 21551322] [Full Text: https://doi.org/10.1161/CIRCGENETICS.110.959270]
Ritter, M., Oechslin, E., Sutsch, G., Attenhofer, C., Schneider, J., Jenni, R. Isolated noncompaction of the myocardium in adults. Mayo Clin. Proc. 72: 26-31, 1997. [PubMed: 9005281] [Full Text: https://doi.org/10.4065/72.1.26]
Sasse-Klaassen, S., Gerull, B., Oechslin, E., Jenni, R., Thierfelder, L. Isolated noncompaction of the left ventricular myocardium in the adult is an autosomal dominant disorder in the majority of patients. Am. J. Med. Genet. 119A: 162-167, 2003. [PubMed: 12749056] [Full Text: https://doi.org/10.1002/ajmg.a.20075]
Sasse-Klaassen, S., Probst, S., Gerull, B., Oechslin, E., Nurnberg, P., Heuser, A., Jenni, R., Hennies, H. C., Thierfelder, L. Novel gene locus for autosomal dominant left ventricular noncompaction maps to chromosome 11p15. Circulation 109: 2720-2723, 2004. [PubMed: 15173023] [Full Text: https://doi.org/10.1161/01.CIR.0000131865.21260.56]
Stollberger, C., Finsterer, J., Blazek, G. Left ventricular hypertrabeculation/noncompaction and association with additional cardiac abnormalities and neuromuscular disorders. Am. J. Cardiol. 90: 899-902, 2002. [PubMed: 12372586] [Full Text: https://doi.org/10.1016/s0002-9149(02)02723-6]