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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) (UniProtKB – Q5T481 [RBM20_HUMAN]. http://www.uniprot.org/uniprot/Q5T481. Accessed September 2017; PMID: 22466703). 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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

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