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RBM20

Associated disorders

The RBM20 gene is associated with autosomal dominant dilated cardiomyopathy (DCM) (MedGen UID: 416441).

Pathogenic RBM20 variants are associated with 1%-2% of clinical cases of DCM.

The RBM20 gene encodes a ribonucleic acid (RNA) binding protein thought to be essential for regulation and normal gene splicing of some sarcomere genes.

RBM20
OMIM: 613171

Clinical condition
The RBM20 gene is one of many genes associated with non-syndromic, autosomal dominant dilated cardiomyopathy (DCM; MedGen UID: 416441; PMID: 20301486).

DCM is defined by left ventricular dilation and systolic dysfunction, which may lead to heart failure, arrhythmias or conduction system disease, and thromboembolic disease (PMID: 20301486). RBM20-related DCM often results in an arrhythmogenic form of cardiomyopathy (PMID: 20590677). Symptoms may include edema, shortness of breath, fatigue, palpitations, dizziness, syncope, and sudden cardiac arrest/death (PMID: 20301486). The disease may develop at any age, and affected individuals are often asymptomatic until late in the course of the disease (PMID: 20590677, 22004663, 20301486).

Gene information
The RBM20 gene encodes the RNA-binding motif protein 20, which regulates mRNA splicing of a subset of genes involved in cardiac development including titin (TTN) (PMID: “(external)22466703”:http://ncbi.nlm.nih.gov/pubmed/22466703; UniProtKB – Q5T481 [RBM20_HUMAN], http://www.uniprot.org/uniprot/Q5T481. Accessed September 2017). Pathogenic truncating variants in TTN are the leading genetic cause of DCM (PMID: 22335739, 20301486). Specifically, loss of function of the RBM20 protein can lead to expression of a pathologic titin isoform (PMID: 22466703). There is a five-amino-acid hot spot in the RBM20 protein arising from exon nine (PMID: 19712804, 23886709).

Inheritance
Pathogenic variants in RBM20 exhibit autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing that variant on to their offspring. RBM20 pathogenic variants exhibit reduced penetrance and variable expression, meaning that not everyone who inherits the pathogenic variant and a predisposition for disease will develop DCM (PMID: 21787999). Some individuals may never develop the disease and others may be affected but not show an abnormality on echocardiogram or ECG/EKG analysis until later in the disease course. (PMID: 20301486)

Management
It is recommended to manage DCM by a combination of medication, device therapy, and heart transplantation. Pre-symptomatic treatment may forestall symptoms and improve survival and quality of life. Surveillance of affected individuals includes periodic physical exam, echocardiogram, and ECG/EKG. It is recommended that management decisions be made based on clinical presentation, symptoms, and family history (PMID: 19254666).

Pregnancy is contraindicated in most cases for women with DCM. Pregnant women with DCM or a family history of DCM should be followed by a high-risk obstetrician (PMID: 20301486).

Genetic testing is recommended for at-risk family members of an individual with a DCM-causing pathogenic variant (PMID: 21787999). Serial clinical screening by medical history, physical exam, echocardiogram, and ECG/EKG for at-risk family members is also recommended (PMID: 19254666).

Review date: September 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
RBM20 NM_001134363.2