ORPHA: 154; DO: 0110431;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q35 | Cardiomyopathy, dilated, 1I | 604765 | Autosomal dominant | 3 | DES | 125660 |
A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-1I (CMD1I) is caused by heterozygous mutation in the DES gene (125660), which encodes desmin, on chromosome 2q35.
For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).
Li et al. (1999) studied a 4-generation Caucasian family segregating autosomal dominant dilated cardiomyopathy. The proband had had cardiomegaly and chronic cardiac failure for more than 5 years, with a left ventricular ejection fraction of 40% and diffuse hypokinesis. His son had cardiomegaly with a left ventricular ejection fraction of 45%. The proband's paternal grandfather had chronic heart failure for more than 2 decades and died at 65 years of age. The proband also had 3 cousins who died between the ages of 15 and 37 years and who had heart failure before death. Individuals had no symptoms of skeletal muscle involvement, and there was no clinical evidence of it. Plasma creatine kinase activity in each individual was consistently within the normal range.
Otten et al. (2010) reported a Dutch family in which a sister and brother and their father had severe biventricular cardiomyopathy. The sister presented at 9 years of age with complete atrioventricular (AV) block and slow ventricular escape rhythm; a pacemaker was implanted at 19 years of age, at which time increased diameter of the left atrium and right ventricle was noted. Left ventricular ejection fraction progressively decreased, and endomyocardial biopsy at age 21 years showed slightly hypertrophic cardiomyocytes with extensive fibrosis and focal infiltrations of inflammatory cells. She had progressive dyspnea and died at age 28 from heart failure. She had never complained about muscle weakness, and no neurologic examination was ever performed. Her brother had total AV block at 17 years of age and had a pacemaker implanted at age 19, at which time he had dilation of the left and right atria with normal systolic left ventricular function (ejection fraction, 57%). Endomyocardial biopsy showed findings identical to those in his sister, and his left ventricular function progressively deteriorated, to an ejection fraction of 35% at 26 years of age. He also developed atrial fibrillation and hypotension, and died at age 27 years. Their father was diagnosed with cardiomyopathy at age 19 and had total AV block at age 20, with implantation of a pacemaker at age 21. He had progressive fatigue and dyspnea, and died at 31 years of age; postmortem examination showed a severely enlarged and dilated heart with extensive circumferential fibrosis and little remaining myocardial tissue. Immunofluorescence analysis of myocardial samples from the sibs showed severe disruption of desmin distribution: no signal was observed at the intercalated discs; rather, desmin formed large cytoplasmic and perinuclear blobs.
Brodehl et al. (2013) studied a large 4-generation family segregating autosomal dominant cardiomyopathy and sudden cardiac death (SCD). The 34-year-old female proband presented with atrial flutter, variable AV conduction, and biatrial dilation. Echocardiography showed normal left ventricular systolic function with an ejection fraction of 67% and borderline concentric left ventricular hypertrophy. Her family history was remarkable for 10 instances of SCD, including 1 sister and 2 brothers who all died in their teens; 2 paternal cousins who died at ages 13 and 30 years; 2 paternal second cousins who died at 13 years; and 3 paternal aunts who died in the fourth and fifth decades of life. In addition, her father and paternal grandfather both died due to cardiomyopathy, at ages 33 and 45, respectively. Given the strong family history of SCD, the proband underwent placement of a cardioverter-defibrillator. She had no signs of myopathy; no neurologic examination or skeletal muscle studies were reported.
Miyamoto et al. (2001) reported 3 unrelated Japanese men with dilated cardiomyopathy and a mutation in the DES gene. Ages at diagnosis were 38, 52, and 55 years, and ejection fractions ranged from 21 to 30%. None of the 3 patients showed any clinical evidence of skeletal muscle involvement on physical examination, and none had abnormal serum levels of creatine kinase or a myopathic pattern on electromyelogram. Cardiac biopsy specimens from the 3 patients showed nonspecific histopathologic findings consistent with dilated cardiomyopathy, including mild interstitial fibrosis and cellular hypertrophy. Desmin immunostaining was performed in 1 case and showed desmin-reactive deposits, characteristic of desmin mutation-associated myopathy. The authors noted that long-term follow-up in the 3 patients showed inconsistent results despite similar standard treatment: in the first patient the disease was unchanged, the second showed remarkable improvement, and the third had marked exacerbation.
Li et al. (1999) used a candidate gene approach to identify genetic defects in 44 unrelated probands with autosomal dominant dilated cardiomyopathy. In 1 family with pure cardiomyopathy without skeletal myopathy (CMD1I), they identified a heterozygous ile451-to-met substitution in the DES gene (125660.0005). This mutation was not present in 920 control chromosomes.
In a Dutch brother and sister with severe biventricular cardiomyopathy and no known skeletal myopathy, who were negative for mutation in 6 CMD-associated genes, Otten et al. (2010) identified heterozygosity for a missense mutation in the DES gene, R454W, that was not found in their unaffected mother. The authors noted that R454W had previously been reported (Bar et al., 2007) in a sporadic French patient of North African origin with hypertrophic cardiomyopathy and skeletal myopathy; however, the patient also carried a Q74K variant in the myotilin gene (MYOT; 604103) that was considered to be 'conditionally pathogenic' because it had also been found in normal controls.
In the proband of a large 4-generation family segregating autosomal dominant dilated cardiomyopathy and sudden cardiac death, who was negative for pathogenic mutations in 11 CMD-associated genes and 8 genes associated with arrhythmogenic right ventricular cardiomyopathy (ARVC; see 107970), Brodehl et al. (2013) identified heterozygosity for a missense mutation, A120D, in the DES gene. The mutation was also present in a paternal aunt with Ebstein anomaly (224700) who had undergone cardiac transplantation and in an asymptomatic paternal second cousin who had a severely dilated right atrium on examination; it was not found in 6 unaffected family members, in 394 controls, in publicly available databases, or in more than 12,500 alleles from the NHLBI Exome Sequencing Project. In vitro functional analysis of the A120D variant, which occurs at a highly conserved residue, revealed a severe intrinsic filament formation defect causing cytoplasmic aggregates in cell lines and of the isolated recombinant protein. Affected individuals in this family apparently did not exhibit signs of myopathy, but no neurologic examination or skeletal muscle studies were reported.
In a 27-year-old Iranian man diagnosed with restrictive cardiomyopathy, born of first-cousin parents, Brodehl et al. (2019) analyzed a panel of 174 cardiomyopathy-associated genes and identified homozygosity for a missense mutation in the DES gene (Y122H). Echocardiography showed severe biatrial enlargement with normal-sized ventricles and a restrictive flow pattern. In addition, he underwent placement of a permanent pacemaker at age 22 due to severe bradycardia associated with third degree atrioventricular block. A paternal aunt was reported to have had skeletal myopathy without cardiac involvement, but family members were unavailable for evaluation. The proband gave a history of having been active in sports during his teenage years; no neurologic examination or skeletal muscle studies were reported. The authors noted that a different mutation at the same codon (Y122C) had been reported by Walsh et al. (2017) in a patient with arrhythmogenic right ventricular cardiomyopathy (ARVD; see 107970); no further details on that patient were reported. Brodehl et al. (2019) performed cell transfection experiments that demonstrated severe aggregate formation with both the Y122H and Y122C mutants, in contrast to formation of regular intermediate filaments observed with wildtype desmin.
Miyamoto et al. (2001) screened exon 8 of the DES gene in a cohort of 265 Japanese probands with CMD and identified 3 unrelated men who were heterozygous for the previously reported I451M mutation, which was not found in 259 controls. Compared to the CMD patients without the I451M mutation, the 3 patients were younger at diagnosis and had lower ejection fraction and fractional shortening. None of the 3 patients showed any clinical evidence of skeletal muscle involvement on physical examination, and none had abnormal serum levels of creatine kinase or a myopathic pattern on electromyelogram. All 3 cases were sporadic; in the 1 family in which parental DNA was available, the mutation was shown to have arisen de novo. Haplotype analysis indicated that 2 of the men might have been ancestrally related.
Taylor et al. (2007) analyzed the DES gene in 425 probands with CMD and identified 5 missense mutations in 6 sporadic patients, 3 of which were likely pathogenic (see, e.g., 125660.0021). None of the patients had overt skeletal muscle involvement, although none had a skeletal muscle biopsy and formal neurologic assessment was not performed in most patients. Functional analysis of the 3 likely pathogenic mutations demonstrated severe disruption of desmin filament assembly.
Bar, H., Goudeau, B., Walde, S., Casteras-Simon, M., Mucke, N., Shatunov, A., Goldberg, Y. P., Clarke, C., Holton, J. L., Eymard, B., Katus, H. A., Fardeau, M., Goldfarb, L., Vicart, P., Herrmann, H. Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies. Hum. Mutat. 28: 374-386, 2007. [PubMed: 17221859] [Full Text: https://doi.org/10.1002/humu.20459]
Brodehl, A., Dieding, M., Klauke, B., Dec, E., Madaan, S., Huang, T., Gargus, J., Fatima, A., Saric, T., Cakar, H., Walhorn, V., Tonsing, K., and 11 others. The novel desmin mutant p.A120D impairs filament formation, prevents intercalated disk localization, and causes sudden cardiac death. Circ. Cardiovasc. Genet. 6: 615-623, 2013. [PubMed: 24200904] [Full Text: https://doi.org/10.1161/CIRCGENETICS.113.000103]
Brodehl, A., Pour Hakimi, S. A., Stanasiuk, C., Ratnavadivel, S., Hendig, D., Gaertner, A., Gerull, B., Gummert, J., Paluszkiewicz, L., Milting, H. Restrictive cardiomyopathy is caused by a novel homozygous desmin (DES) mutation p.Y122H leading to a severe filament assembly defect. Genes (Basel) 10: E918, 2019. Note: Electronic Article. [PubMed: 31718026] [Full Text: https://doi.org/10.3390/genes10110918]
Li, D., Tapscoft, T., Gonzalez, O., Burch, P. E., Quinones, M. A., Zoghbi, W. A., Hill, R., Bachinski, L. L., Mann, D. L., Roberts, R. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation 100: 461-464, 1999. [PubMed: 10430757] [Full Text: https://doi.org/10.1161/01.cir.100.5.461]
Miyamoto, Y., Akita, H., Shiga, N., Takai, E., Iwai, C., Mizutani, K., Kawai, H., Takarada, A., Yokoyama, M. Frequency and clinical characteristics of dilated cardiomyopathy caused by desmin gene mutation in a Japanese population. Europ. Heart J. 22: 2284-2289, 2001. [PubMed: 11728149] [Full Text: https://doi.org/10.1053/euhj.2001.2836]
Otten, E., Asimaki, A., Maass, A., van Langen, I. M., van der Wal, A., de Jonge, N., van den Berg, M. P., Saffitz, J. E., Wilde, A. A. M., Jongbloed, J. D. H., van Tintelen, J. P. Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks. Heart Rhythm 7: 1058-1064, 2010. [PubMed: 20423733] [Full Text: https://doi.org/10.1016/j.hrthm.2010.04.023]
Taylor, M. R. G., Slavov, D., Ku, L., Di Lenarda, A., Sinagra, G., Carniel, E., Haubold, K., Boucek, M. M., Ferguson, D., Graw, S. L., Zhu, X., Cavanaugh, J., Sucharov, C. C., Long, C. S., Bristow, M. R., Lavori, P., Maestroni, L., BEST (Beta-Blocker Evaluation of Survival Trial) DNA Bank. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation 115: 1244-1251, 2007. [PubMed: 17325244] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.106.646778]
Walsh, R., Thomson, K. L., Ware, J. S., Funke, B. H., Woodley, J., McGuire, K. J., Mazzarotto, F., Blair, E., Seller, A., Taylor, J. C., Minikel, E. V., Exome Aggregation Consortium, MacArthur, D. G., Farrall, M., Cook, S. A., Watkins, H. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet. Med. 19: 192-203, 2017. [PubMed: 27532257] [Full Text: https://doi.org/10.1038/gim.2016.90]