A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-1DD is caused by heterozygous mutation in the RBM20 gene (613171) on chromosome 10q25.

For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

Brauch et al. (2009) studied 2 large multigenerational European American families with dilated cardiomyopathy (CMD). In 'kindred DC-12,' the patriarch, who was of Scottish ancestry, died suddenly at 39 years of age. Ten family members developed documented CMD, 2 as young children; the mean age at diagnosis was 30 years. Two underwent cardiac transplantation as young adults, and all but 3 had died of their disease (mean age at death, 37.7 years). In 'kindred DC-35,' which was of Norwegian ancestry, the proband's father died suddenly at 29 years of age. Twelve relatives had documented CMD, with a mean age at diagnosis of 41.3 years, and 5 others had suspected CMD based on sudden death and/or history alone (mean age at death, 45.7 years). Five living relatives with CMD received an implantable cardioverter-defibrillator (ICD).

Li et al. (2010) described CMD patients with mutations in the RBM20 gene. One proband (Pedigree B) presented with a flu-like illness that prompted a chest x-ray examination, which revealed remarkable cardiomegaly. She was diagnosed with CMD at 46 years of age, and at age 53, she had decompensated heart failure; she died later that year. In another family (Pedigree D), the asymptomatic proband underwent clinical screening at age 43 years due to a strong family history of cardiovascular disease and was diagnosed with CMD, frequent ventricular premature beats, and ventricular tachycardia. Family history included early deaths in her sister (age 25) and 2 nieces (ages 14 and 16 years) from arrhythmias and/or complications after heart transplantation. While awaiting heart transplantation, the proband died at age 64 from strokes related to a left ventricular assist device. Her son was diagnosed with CMD at age 23, and exhibited interventricular conduction delay and nonspecific ST-T wave changes on electrocardiography. In a third family (Pedigree E), the proband was a 51-year-old woman diagnosed with CMD after exhibiting symptoms that included chest tightness, difficulty breathing, and irregular heart rate. Her 30-year-old daughter had syncope and heart failure and was rescued from cardiac arrest by an ICD. Her 25-year-old son was reported to have left ventricular enlargement and CMD.

Brauch et al. (2009) performed genomewide linkage analysis followed by regional high-density genotyping in 2 large multigenerational CMD families and obtained peak 2-point lod scores of 3.55 at marker D10S1269 for kindred DC-12 and 4.55 at marker D10S221 for kindred DC-35. Fine mapping in kindred DC-12 identified a disease-associated haplotype in a 19.3-Mb interval on chromosome 10q25.1-q26.2, with a peak multipoint lod score of 3.62 for all subjects under an assumption of 100% penetrance and of 2.67 for affected subjects only; a recombination event narrowed the critical region to 4.6 Mb. Fine mapping in kindred DC-35 identified an overlapping disease-associated haplotype spanning 22.8 Mb, with a peak multipoint lod score of 4.89 for all subjects under an assumption of 100% penetrance and of 3.58 for affected subjects only. The haplotypes were different for each family, suggesting that they did not share common ancestry, but the overlapping disease loci raised the possibility of a shared CMD gene.

In 2 large multigenerational families with dilated cardiomyopathy (CMD) mapping to chromosome 10q25-q26, Brauch et al. (2009) analyzed candidate genes and identified 2 different heterozygous missense mutations in exon 9 of the RMB20 gene (613171.0001 and 613171.0002, respectively) that cosegregated with disease and were not found in 480 ethnically matched controls. DHPLC analysis of the RBM20 gene in a cohort of 278 CMD patients revealed 6 additional families with heterozygous mutations in the RBM20 gene (613171.0003-613171.0005); the mutations all clustered within exon 9 of the RBM20 gene, cosegregated with disease, and were absent in controls. There were 5 female family members who inherited a mutation but did not fulfill diagnostic criteria, 4 of whom had left ventricular enlargement but a normal ejection fraction and 1 with a normal echocardiogram.

Using DNA from 312 CMD probands, Li et al. (2010) analyzed exons 6 through 9 of the RBM20 gene and identified heterozygous missense mutations in 6 unrelated probands (see, e.g., 613171.0002, 613171.0004, and 613171.0006).

Brauch et al. (2009) stated that mutations in RBM20 were associated with clinically aggressive CMD: the 39 mutation-positive patients in the 8 families were diagnosed 9 years earlier than a comparable series of patients with sporadic and familial CMD (mean age at diagnosis, 35.9 vs 45.2 years); death occurred in 11 patients at a mean age of 45.2 years, 4 underwent cardiac transplantation, and 8 received an ICD. The malignant nature of RBM20-associated CMD was further illustrated in the 32 family members with CMD by history, of whom 13 died suddenly at a mean age of 32.7 years, 3 underwent cardiac transplantation, and 3 received an ICD. There were no consistent electrocardiographic features associated with RBM20 mutation, although 9 mutation-positive patients had ventricular tachycardia.